Abstract
Objective
To compare the urine protein–creatinine ratio with urinalysis to predict significant proteinuria (≥300 mg per day).
Study Design
A total of 116 paired spot urine samples and 24-h urine collections were obtained prospectively from women at risk for preeclampsia. Urine protein–creatinine ratio and urinalysis were compared to the 24-h urine collection.
Result
The urine protein–creatinine ratio had better discriminatory power than urinalysis: the receiver operating characteristic curve had a greater area under the curve, 0.89 (95% confidence interval (CI) 0.83 to 0.95) vs 0.71 (95% CI 0.64 to 0.77, P<0.001). When matched for clinically relevant specificity, urine protein–creatinine ratio (cutoff ≥0.28) is more sensitive than urinalysis (cutoff ≥1+): 66 vs 41%, P = 0.001 (with 95 and 100% specificity, respectively). Furthermore, the urine protein–creatinine ratio predicted the absence or presence of proteinuria in 64% of patients; urinalysis predicted this in only 19%.
Conclusion
The urine protein–creatinine ratio is a better screening test. It provides early information for more patients.
Keywords: pregnancy, urinalysis, urine protein, creatinine ratio, proteinuria, preeclampsia, sensitivity and specificity
Introduction
The diagnosis of preeclampsia is determined by the presence of elevated blood pressure and significant proteinuria (≥300 mg per 24 h) after the 20th week of gestation.1 The gold standard for measuring proteinuria is the 24-h urine collection. Unfortunately, the 24-h urine collection takes an entire day to collect and is, therefore, not available to guide clinical decisions upon first evaluation. A rapid screening test to predict 24-h proteinuria, in combination with other presenting signs and symptoms, can help a clinician determine the appropriate amount of surveillance and guide care during the initial 24-h period. Traditionally, the dipstick urinalysis has been used as this screening test.2
The dipstick urinalysis measures the concentration of protein in the urine and is susceptible to fluctuations in the water content of the urine. Dilute urine may underestimate the amount of protein that would be collected in a 24-h urine collection, whereas concentrated urine may overestimate it. Prior studies have reported that dipstick urinalysis has varying degrees of accuracy, with sensitivities ranging from 22 to 82%. Specificities also vary widely.2–5 Differences in methodology contribute to this large discrepancy. For example, automated dipstick urinalysis is more specific for predicting 24-h proteinuria than is ward dipstick urinalysis.6 Furthermore, discrepancies in the reported sensitivity and specificity of the dipstick urinalysis may be due to differences in the spectrum of illness in the populations studied or the time of day that the spot urine was collected.
Recently, the urine protein–creatinine ratio has been considered important for predicting proteinuria. It compares the spot urine protein excretion to the spot urine creatinine excretion, thereby normalizing protein excretion to the glomerular filtration rate. Thus, the urine protein–creatinine ratio is not subject to variation due to hydration status. In pregnant women, the urine protein–creatinine ratio and the 24-h urine are highly correlated.6–13 Many studies have evaluated the urine protein– creatinine ratio but, they differ in their recommended cutoffs and differ in their assessment of the test's utility.6–9,12,13 Different methodologies, such as the spectrum of illness in the population studied, retrospective study design,9 exclusion of patients with comorbid illness,9,13 and nonexclusion of incomplete or infected samples6–13 probably account for these discrepancies.
No study has directly compared the diagnostic ability of the automated dipstick urinalysis to that of the urine protein–creatinine ratio using the same group of subjects, which would allow appropriate statistical comparisons. In this study, we directly compared the two tests in a prospective fashion on a group of women being evaluated for preeclampsia, including those with comorbid illness to determine which was more predictive of 24-h proteinuria.
Methods
This prospective study was performed on the Labor and Delivery unit at Stanford University Hospital from September 2002 to March 2004 after approval by the Institutional Review Board, Medical Human Subjects Panel. Written informed consent was obtained from all participating patients. To mimic the experience of treating physicians we included all women being evaluated for preeclampsia, regardless of the alerting sign or symptom, suspected severity or comorbid conditions. Study patients underwent initial triage on the Labor and Delivery unit. Most women completed the 24-h urine collection as outpatients, but some remained in the unit as clinically indicated. The study design allowed for patients to be enrolled when they presented to Labor and Delivery for an independent evaluation of preeclampsia. Therefore, women could be enrolled more than once. There were 155 enrollments. Of these, 19 were excluded because the 24-h urine was not done, 4 because the urinalysis was not done and 6 because the urine protein– creatinine ratio was not done. Six were excluded because the 24-h urine was not complete or the collection was improper by the criteria below. Four were excluded because the urinalysis had>10 white blood cells (WBCs) per high-power field (h.p.f.) on microscopy, concerning for contamination. A total of 116 enrollments from 95 women were ultimately included in the study. Thus, 21 of the 116 samples were from women who were enrolled in the study more than once.
The main measures were the urinary protein concentration by automated dipstick urinalysis, the urinary protein to urinary creatinine ratio by random (spot) direct measurement and the 24-h urinary protein excretion by a 24-h urine collection. The urinalysis and the urine protein–creatinine ratio were usually obtained immediately before the 24-h urine collection was begun. If that sample was not available at the time of enrollment, a sample was obtained immediately after the 24-h collection. All samples were collected via clean catch unless the membranes had been ruptured, in which case specimens were obtained by catheter.
Given that outpatient and inpatient urine collections may have been collected with different degrees of completeness and/or contamination, subjects were excluded if the urinalysis contained >10 WBCs per h.p.f., if a catheter was not used after membrane rupture or if an outpatient 24-h urine collection was incomplete. A complete collection was defined as having a total creatinine of >1000 mg (850 mg for obese women) or a total creatinine of 13 mg per kg body weight.14
The urinary protein and creatinine were measured using Synchron LX Systems (Beckman Coulter Inc., Fullerton, CA, USA), which uses the pyrogallol red/molybdate and Jaffe rate methods, respectively. The automated dipstick urinalysis was performed with Iris test strips and either the IRIS 500 (IRIS Inc., Chatsworth, CA, USA) or Autionmax (Arcray Inc., Kyoto, Japan), autoanalyzers using 3′3″5′5″-tetrachlorophenol-3,4,5,6-tetrabromosulfopthalein, a protein error of pH indicator. These machines were calibrated such that 1 + protein = 30 mg per 100 ml, 2 + protein = 100 mg per 100 ml, 3 + protein = 300 mg per 100 ml and 4 + protein = 1000 mg per 100 ml. Trace protein was not reported by these machines. All measurements were performed by laboratory technicians blinded to the clinical status of the study patients.
Statistical analysis
The strengths of the correlation between the automated dipstick urinalysis and 24-h proteinuria and the urine protein–creatinine ratio and 24-h proteinuria were determined by Spearman's correlation coefficients with corresponding 95% confidence intervals (CI).
Significant proteinuria was defined as ≥ 300 mg of protein in the 24-h urine collection, as recommended by the International Society for the Study of Hypertension in Pregnancy and the American College of Obstetrics and Gynecology.1,15 The sensitivity and specificity16 as well as the positive and negative predictive values17 were calculated using each observed level of the urinalysis and the urine protein–creatinine ratio as the threshold for a positive test with the 24-h collection as the reference standard. Differences in selected sensitivities and specificities were examined using the McNemar's test. The likelihood ratios (LRs) for ranges of the urine protein–creatinine ratio and urinalysis were calculated.18 Additionally, we examined the test characteristics for predicting a severe level of proteinuria of 5000 mg or greater.
The relationship between sensitivity and the false-positive rate (1—specificity) for both the urinalysis and the urine protein–creatinine ratio was evaluated by constructing receiver operating characteristic (ROC) curves for both measures. As a summary of the diagnostic utility of the urinalysis and the urine protein–creatinine ratio, the areas under the ROC curves were calculated and directly compared using the method described by Delong et al.19 Data analysis was performed using STATA statistical software (Release 8; Stata Corp., College Station, TX, USA).
To examine whether a lack of independence due to some subjects contributing more than one set of paired spot urine and 24-h urine samples led to inaccurate estimates in our analysis, a sensitivity analysis was performed comparing the statistical outcome of the data from the initial 116 samples to that of 95 samples (using only first samples if there had been additional enrollments).
Results
Population studied
A total of 116 paired samples were evaluated. Of those 48% had significant proteinuria. Forty-one percent were from primigravidas. In total, 41% of the samples were from Caucasian women, 31% from Hispanic women, 16% from Asian women and 12% from African-American women. Many subjects had medical conditions that predisposed them to preeclampsia (Table 1).
Table 1.
Demographic and clinical characteristics of study participants by presence or absence of significant proteinuria in a 24-h urine collection (n=116)
| Characteristic | <300 mg protein per 24 h (n = 60) | ≥300 mg protein per 24 h (n = 56) |
|---|---|---|
| Age, mean (s.d.) | 30.8 (6.2) | 30.8 (6.5) |
| Caucasian, no. (%) | 25 (41.7) | 22 (39.3) |
| Primigravida, no. (%) | 19 (32.7) | 22 (39.3) |
| Weight lbs, mean (s.d.) | 189.5 (37.1) | 193.9 (41.5) |
| High systolic blood pressure, mean (s.d.) | 141.4 (13.1) | 143.4 (16.3) |
| High diastolic blood pressure, mean (s.d.) | 89.3 (11.3) | 91.5 (12.8) |
| Chronic hypertension, no. (%) | 10 (16.7) | 16 (28.6) |
| Diabetes mellitusa, no. (%) | 7 (11.7) | 1 (1.8) |
| Total 24-h protein, median (IQR) mg | 210 (165–242) | 580 (390–1246) |
Abbreviations: IQR, interquartile range; lbs, pounds.
Includes pregestational and gestational diabetes.
Correlation of the urine protein–creatinine ratio vs the urinalysis to 24-h proteinuria
Both the urine protein–creatinine ratio and the urinalysis were correlated to the gold standard, 24-h proteinuria. The correlation coefficient for the urine protein–creatinine ratio was 0.83 (95% CI 0.76 to 0.88). For the urinalysis, it was 0.64 (95% CI 0.52 to 0.74).
Receiver operating characteristic curves
The ROC curves for both the urine protein–creatinine ratio and the urinalysis are presented in Figure 1. A diagnostic test with an area under the ROC curve closest to 1.0 has the best discriminatory power. The area under the ROC curve for the urine protein–creatinine ratio was 0.89 (95% CI 0.83 to 0.95), and the area under the ROC curve for the urinalysis was 0.71 (95% CI 0.64 to 0.77). The areas under these curves were significantly different (P<0.001).
Figure 1.
Receiver operating characteristic curves (ROCs) for the urine protein–creatinine ratio (a) and for the urinalysis (b). The area under the ROC curve for the urine protein–creatinine ratio is 0.89 (95% CI 0.83 to 0.95) and the area under the ROC curve for the urinalysis is 0.71 (95% CI 0.64 to 0.77). The areas under these curves are significantly different (P<0.001). Selected values for each measure, along with the sensitivity or specificity, are highlighted.
Sensitivity and specificity of the urine protein–creatinine ratio and the urinalysis for predicting significant proteinuria (≥300 mg proteinuria per 24-h period)
The urine protein–creatinine ratio is the more sensitive test for predicting 24-h proteinuria compared to the urinalysis, even when matched for specificity. Table 2 demonstrates the sensitivity and specificity for both tests at selected cutoffs. These points were selected because they demonstrate the range from maximum sensitivity to maximum specificity. Note that ‘trace’ proteinuria is not reported by automated dipstick machines.
Table 2.
Sensitivity, specificity, positive predictive value and negative predictive value for selected cutoffs for the urine protein–creatinine ratio and the urinalysis for predicting ≥300 mg protein per 24 h urine
| Test result | Sensitivity (%) | Specificity (%) | PPV (%) | NPV (%) |
|---|---|---|---|---|
| UPCR | ||||
| ≥0.15a | 96 | 53 | 66 | 94 |
| ≥0.17 | 91 | 58 | 67 | 88 |
| ≥0.19 | 89 | 70 | 74 | 88 |
| ≥0.24 | 73 | 87 | 84 | 78 |
| ≥0.28 | 66 | 95 | 93 | 75 |
| ≥0.39 | 55 | 100 | 100 | 71 |
| UA | ||||
| ≥Negative | 100 | 0 | 48 | –b |
| ≥1+ | 41 | 100 | 100 | 65 |
| ≥2+ | 23 | 100 | 100 | 58 |
| ≥3+ | 11 | 100 | 100 | 55 |
Abbreviations: UA, urinalysis; UPCR, urine protein–creatinine ratio.
Using a cutoff of ≥0.15, two subjects with significant 24-h proteinuria (304 and 336 mg) were missed.
This number could not be calculated due to 0 in the denominator.
The sensitivity for the urine protein–creatinine ratio varied depending on the cutoff used. We highlight two clinically useful cutoffs derived from the ROC curve, one that maximizes sensitivity and the other that maximizes specificity. A cutoff of ≥0.15 had a sensitivity of 96% (95% CI 87 to 99%) and a specificity of 53% (95% CI 40 to 66%). A cutoff of ≥0.28 had a sensitivity of 66% (95% CI 52 to 78%) and a specificity of 95% (95% CI 86 to 99%). Note that a cutoff of ≥0.19 maximizes both sensitivity (89, 95% CI 78 to 96%) and specificity (70, 95% CI 59 to 83%), but significantly compromises both measures.
The sensitivity for the urinalysis ranged from 11 to 41% depending on the cutoff used (Table 2). Greater than or equal to 1 + proteinuria on the dipstick had a sensitivity of 41% (95% CI 28 to 55%) and a specificity of 100% (95% CI 93 to 100%).
These data demonstrate that when using a cutoff of ≥0.15, the urine protein–creatinine ratio is significantly more sensitive than the urinalysis (96 vs 41%, P<0.001). Even when matching the two tests for clinically relevant specificity with a urine protein–creatinine ratio cutoff of ≥0.28 and a urinalysis cutoff of ≥1 + (specificity is 95 and 100%, respectively), the sensitivity of the urine protein–creatinine ratio is better than that of the urinalysis (66 vs 41%, P = 0.001).
Likelihood ratios for the urine protein–creatinine ratio and the urinalysis
Unlike predictive values, LRs are less subject to variation in the prevalence of disease in a given population.17 We list the LRs for ranges of each test (Table 3). In general, a diagnostic test with an LR of>10 or <0.10 changes pretest probability dramatically and is considered a strong diagnostic test.20
Table 3.
Likelihood ratios for the urine protein–creatinine ratio and the urinalysis for different ranges of test results
| Test result | Likelihood ratioa (95% CI) | Interpretation |
|---|---|---|
| UPCR | ||
| <0.15 | 0.07 (0.02–0.27) | Negative |
| 0.15–0.27 | 0.73 (0.44–1.2) | Indeterminate |
| ≥0.28 | 13.21 (4.3–40.5) | Positive |
| UA | ||
| Negative | 0.59 (0.47–0.73) | Indeterminate |
| ≥1+ | 49.29 (3.1–792.8) | Positive |
Abbreviations: UA, urinalysis; UPCR, urine protein–creatinine ratio.
0.05 was added to empty cells to allow for the calculation of the likelihood ratios.
Likelihood ratios calculated for values of the urine protein–creatinine ratio <0.15 and ≥0.28 have a large effect on pretest probability. For example, with a urine protein–creatinine ratio of <0.15 (LR = 0.07, 95% CI 0.02 to 0.27), pretest probabilities of 40, 50 and 60% transform to posttest probabilities of 4, 6 and 9%, respectively. Similarly, with values ≥0.28 (LR = 13.2, 95% CI 4.3 to 40.1), pretest probabilities of 40, 50 and 60% transform to posttest probabilities of 90, 93 and 95%, respectively. A urinalysis of ≥1 + (LR = 49.7, 95% CI 3.1 to 792.3) also has an LR that is strongly diagnostic.
However, values of the urine protein–creatinine ratio from 0.15 to 0.27 (LR = 0.73, 95% CI 0.44 to 1.20) and a negative urinalysis (LR = 0.59, 95% CI 0.47 to 0.73) do not significantly affect pretest probability. Therefore, urine samples with these results are indeterminate.
Thus, the urine protein–creatinine ratio is useful diagnostically when the value is <0.15 or ≥0.28, but is indeterminate in the middle range. Similarly, the urinalysis is useful when the value is ≥1 + protein, but is indeterminate when it is negative for protein. In our study the urine protein–creatinine ratio was diagnostic in 64% our samples, whereas, the urinalysis was diagnostic in only 19% of our samples (P<0.001).
Sensitivity and specificity of the urine protein–creatinine ratio and the urinalysis for predicting severe proteinuria (≥5000 mg proteinuria per 24-h period)
Sensitivities, specificities and positive and negative predictive values were calculated for many cutoffs of the urine protein–creatinine ratio and each cutoff of the urinalysis to demonstrate the accuracy of each test for predicting ≥5000 mg proteinuria per 24-h period (Table 4). Only three patients in our study had proteinuria ≥5000 mg of protein. As a screening test for identifying patients who may have severe proteinuria, the urine protein–creatinine ratio and the urinalysis are very good. They also both have good specificity, in particular the urine protein–creatinine ratio ≥5.0 and the urinalysis ≥3+. In fact, to predict severe proteinuria it appears that the urine protein–creatinine ratio is unlikely to add utility to the urinalysis alone. Caution should be used in using spot urine studies rather than 24-h urine collections to make a diagnosis of severe proteinuria because this analysis is limited by the relatively few number of patients with severe proteinuria in this study and, therefore, the inability to accurately describe a range.
Table 4.
Sensitivity, specificity, positive predictive value and negative predictive value for selected cutoffs for the urine protein–creatinine ratio and the urinalysis for predicting ≥5000 mg protein per 24 h urine
| Test result | Sensitivity (%) | Specificity (%) | PPV (%) | NPV (%) |
|---|---|---|---|---|
| UPCR | ||||
| ≥2 | 100 | 96 | 38 | 100 |
| ≥3 | 100 | 97 | 50 | 100 |
| ≥4 | 100 | 98 | 60 | 100 |
| ≥5 | 100 | 100 | 100 | 100 |
| ≥13.53 | 67 | 100 | 100 | 99 |
| UA | ||||
| ≥Negative | 100 | 0 | 3 | −a |
| ≥1+ | 100 | 83 | 14 | 100 |
| ≥2+ | 100 | 92 | 25 | 100 |
| ≥3+ | 100 | 98 | 60 | 100 |
Abbreviations: UA, urinalysis; UPCR, urine protein–creatinine ratio.
This number could not be calculated due to 0 in the denominator.
Sensitivity analysis
Given concern that 21 paired samples from our cohort were from patients who previously contributed samples, we conducted a sensitivity analysis comparing the results of our initial cohort to the cohort minus these 21 samples. Each statistic reported above was calculated for each group, including Spearman's correlation coefficients, the area under the ROC curves, sensitivity and specificity for chosen cutoffs, and LRs for chosen ranges. All of these test results were identical or nearly identical to the values calculated for the entire study group. As expected, the CIs around sensitivity, specificity and LRs were slightly wider for the group with fewer samples.
Discussion
Our study demonstrated that the urine protein–creatinine ratio can be more sensitive than the automated dipstick urinalysis, and therefore, is the better screening test (96 vs 41%, P<0.001). The urinalysis is very specific, but at its most sensitive diagnostic level (1+) will miss more than half (59%) of patients at risk for preeclampsia. The urine protein–creatinine ratio also allows for early diagnosis in more patients (64 vs 19%, P<0.001).
Other studies have previously evaluated the urine protein–creatinine ratio in pregnancy for its ability to predict 24-h proteinuria at different cutoffs.6–9,12,13 Our data are nearly identical to studies that evaluated a similar patient population, and therefore, should be applicable to institutions screening individuals who are clinically suspicious for preeclampsia.7–9,13 Despite the similarity in data, conclusions regarding the ‘optimal cutoff’ and the whether the urine protein–creatinine ratio is useful have varied. This is because an ‘optimal cutoff’ that simultaneously maximizes sensitivity and specificity (0.19 in our case) significantly compromises each measure. We recommend using two cutoffs. A cutoff of ≥0.15 will increase sensitivity to well above 90%, and a cutoff of ≥0.28 will maximize specificity. The urine protein–creatinine ratio cutoff is thus dictated by the physician's needs.
Our study has limitations. A small number of our spot samples were collected immediately after the 24-h urine specimen rather than before. We do not think that this alters our ability to compare the two tests given that the paired urinalysis and urine protein– creatinine ratios were collected at the same time in relation to the 24-h urine collection. Therefore, the direct comparison between the two tests was achieved because the timing of the sample collection was consistent within subjects. It is also important to emphasize that these results demonstrate that the urine protein–creatinine ratio can detect significant 24-h proteinuria (≥300 mg per 24 h) better than the urinalysis, but this study does not address whether the urine protein–creatinine ratio can distinguish between mild and severe preeclampsia by predicting the extent of proteinuria. A 24-h urine may still be needed in settings where the diagnosis of preeclampsia or severe preeclampsia by proteinuria would imply a preterm delivery.
Concern has been raised that the urine protein–creatinine ratio may be effected by body type or by race, as people with higher muscle mass have more total urinary creatinine excretion and nonpregnant African Americans may have a higher concentration of urine creatinine. It is unclear how these differences effect the validity of the urine protein–creatinine ratio in different subpopulations.21 Unfortunately, our study was underpowered to conduct appropriate stratified analyses by race/ethnicity to address these issues. Future studies should be done to address these variations.
On the basis of our study results, we recommend a two-step triage algorithm to identify patients with preeclampsia (Figure 2). On initial screen, an automated dipstick urinalysis should be performed. If the urinalysis has 1+ protein or greater, the patient most likely has significant proteinuria. If the urinalysis is negative for protein (an indeterminate result), a urine protein–creatinine ratio should be ordered to further define risk. If the urine protein– creatinine ratio is <0.15, the patient most likely does not have significant proteinuria. In this setting, whether the 24-h urine collection is still an appropriate test is debatable and may not be cost effective. If the urine protein–creatinine ratio is ≥0.28, the patient most likely has significant proteinuria. If the urine protein–creatinine ratio is between 0.15 and 0.27, this is an indeterminate result and further evaluation with a 24-h urine collection is warranted.
Figure 2.
Flow diagram of the two-step triage strategy. At triage, an automated dipstick urinalysis should be performed. If it is positive, a patient can be assumed to have significant proteinuria. If it is negative, the test is indeterminate and a urine protein–creatinine ratio should be performed to further define risk. In parentheses are the number of samples in the current study that fell into each category. UPCR, urine protein–creatinine ratio.
This diagnostic algorithm is better at providing more accurate and earlier diagnostic information than the traditional automated dipstick urinalysis alone. With the traditional urinalysis, using ≥1 + as a cutoff, the presence of significant proteinuria was predicted in only 19% of our subjects prior to 24-h urine collection. A negative urinalysis cannot predict the absence of significant proteinuria (LR = 0.59, 95% CI 0.47 to 0.73). Using the urinalysis combined with the urine protein–creatinine ratio, the absence or presence of significant proteinuria was predicted in 66% of patients.
In summary, the urine protein–creatinine ratio may be a useful adjunct test for diagnosis and triage of a patient being evaluated for preeclampsia. Its use as an initial screen in combination with the urinalysis will prevent underdiagnosis of preeclampsia and provide an accurate diagnosis 66% of the time before a 24-h collection is completed. Earlier distinction between preeclampsia and other forms of hypertension in triage may allow for earlier diagnosis and treatment of preeclampsia with a subsequent decrease in morbidity and a decrease in resource utilization.
Acknowledgments
This study was financially supported by the Department of Gynecology and Obstetrics, Stanford University.
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