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Random Urine Protein-Creatinine Ratio to Predict Proteinuria in New-Onset Mild Hypertension in Late Pregnancy

Ragip A. Al, MD^*, Cem Baykal, MD^*, Ozlem Karacay, MD^*, Pinar O. Geyik, PhD, Serpil Altun, MD and Ismail Dolen, MD^*

From the *Departments of Obstetrics and Gynecology and Biochemistry, SSK Ankara Maternity and Women's Health Hospital, and Department of Biostatistics, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Address reprint requests to: R. Atakan Al, Cigdem Mah. 357. Sok, Segmen sitesi A Blok No 7/25, 06530 Karakusunlar, Ankara, Turkey; e-mail: atakanal{at}superonline.com.

	ABSTRACT

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OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy of random urine protein-creatinine ratio for prediction of significant proteinuria ( 300 mg/24 h) in patients with new-onset mild hypertension in late pregnancy.

METHODS: Medical records of 185 consecutive pregnant patients with new onset of mild hypertension in late pregnancy were reviewed. Random urine samples were taken before 24-hour urine collection. The predictive values of the random urine protein-creatinine ratio for diagnosis of significant proteinuria were estimated by using at least a 300-mg protein level within the collected 24-hour urine as the gold standard.

RESULTS: Thirty-nine patients (21%) had significant proteinuria. There was a significant association between 24-hour protein excretion and the random urine protein-creatinine ratio (r_s = 0.56, P < .01). With a cutoff protein-creatinine ratio greater than 0.19 as a predictor of significant proteinuria, sensitivity and specificity were 85% and 73%, respectively. Positive and negative predictive values of the test were 46% and 95%, respectively.

CONCLUSION: The random urine protein-creatinine ratio was a poor predictor for significant proteinuria in patients with new-onset mild hypertension in late pregnancy.

LEVEL OF EVIDENCE: II-3

However, the accuracy of the test as a screening or diagnostic tool still remains unclear and is not preferred during pregnancy. The clinical interpretation of a test depends on predictive values that are strongly correlated with prior probability of the disease. In many studies that investigate random urinary protein-to-creatinine ratio, predictive values of the test are not available.^3–6,8 Although several studies have determined predictive values of the test,^2,7,9,10 either the study populations were not clearly defined or methods of patient recruitment precluded getting a reliable estimate of prior probability of significant proteinuria in the populations under study. Although high sensitivity and specificity values have been reported, the observed predictive values cannot be generalized.

A rapid and valid test may shorten the hospitalization time and provide more efficient inpatient and outpatient proteinuria monitoring in patients with new-onset mild hypertension. The aim of this study was to evaluate predictive values of a random urine protein-creatinine ratio in a large sample of new-onset mild hypertension in late pregnancy.

	MATERIALS AND METHODS

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We reviewed the medical records of pregnant women with new-onset mild hypertension in late pregnancy who were admitted to the perinatology unit of Social Security Institute Ankara Maternity and Women's Health Teaching Hospital. At our unit, women with new-onset hypertension were hospitalized initially for a laboratory evaluation and observation. All women, irrespective to the severity of the disease, were asked to provide a 24-hour urine collection for determination of urinary protein excretion. Between January 2002 and June 2003, as a rapid test, random protein-creatinine ratio was used as a routine clinical test. The study covered this period, and the hospital's ethics committee approved the study.

Hypertensive disorder was classified as either mild or severe. Patients were considered to have mild disease if they had systolic blood pressure elevations of 140 mm Hg or greater or diastolic blood pressure of 90 mm Hg or greater, measured twice at least 6 hours apart. Patients were considered to have severe disease when they developed any of the following: blood pressure 160/110 mm Hg or greater, measured twice at least 6 hours apart; hemolysis, elevated liver enzymes, low platelet count syndrome; thrombocytopenia; eclampsia; or intrauterine growth restriction. These patients with severe hypertensive disorder were excluded from this study. Presence of severe proteinuria ( 5 g in 24 hours) was not used as a criterion of the severity of the disease because it was not known whether proteinuria existed before testing in clinical practice. Patients with chronic hypertension were excluded from study.

All 24-hour urine collections were started between 9 and 12 o'clock in the morning. Adequate 24-hour urine collections were defined as those containing at least 10 mg creatinine/kg in 24 hours. Patients were excluded if they had coexisting urinary tract infection or pre-existing intrinsic renal disease or if an inadequate specimen was collected. All random samples were collected in the morning before the start of the 24-hour urine collection. None of these samples were first-voided morning urine. Samples of creatinine were drawn from all patients at the initiation of the 24-hour urine collection. Urine protein concentration was measured by trichloroacetic acid reaction (coefficient of variation 9%).¹¹ The urinary creatinine test was performed with the Beckman Synchron LX Delta System (Beckman Instruments, Richmond, CA), which uses the Jaffe rate method.¹²

Statistical analyses were performed with SPSS 10.0 (SPSS Inc, Chicago, IL) and MedCalc 7.2 (MedCalc Software, Mariakerke, Belgium) statistical packages. Demographic characteristics of patients by significant proteinuria were compared by t test, ² with Yates’ correction, Fisher exact test, and Mann-Whitney U test, as appropriate. Because normality tests failed, associations between maternal age, gestational age, protein-creatinine ratio, and 24-hour protein excretion were assessed by the Spearman correlation coefficient. Significant proteinuria is defined as 300 mg/24 h or greater in a 24-hour urine collection. Sensitivity, specificity, and predictive values of the random urine protein-creatinine ratio at various cutoffs for prediction of significant proteinuria were estimated using the results of the 24-hour urine collection as the gold standard. A receiver operating characteristic curve was constructed, and the area under the curve was estimated with a 95% confidence interval.¹³

	RESULTS

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A total of 221 consecutive patients with new-onset mild hypertension were identified. Twenty-four–hour urine collection was not available for 17 patients. Nineteen patients with pre-existing intrinsic renal disease, coexisting urinary tract infection, or inadequate urine collection for analysis were excluded from the study. One hundred eighty-five consecutive patients constituted our study group. Demographic characteristics of patients by significant proteinuria are presented in Table 1. The median maternal age was 30 years (range 17–44), and the median gestational age was 32 weeks (range 22–40). Twenty-three patients (12%) were in their second trimester, and 162 (88%) were in their third trimester. Ninety-nine women (54%) were nulliparous. Median blood creatinine level was 0.7 mg/dL (range 0.5–1.2). Twenty-two patients had a blood creatinine level of 1 mg/dL or greater.

Thirty-nine patients (21%) had significant proteinuria in their 24-hour urine collection. The median protein level was 1.6 g (range 0.3–8.2) in 24-hour urine of patients who had significant proteinuria. Sixteen patients (41%) had a 24-hour protein excretion of 2 g or greater, and only 3 patients (8%) had a 24-hour protein excretion of 5 g or greater.

Figure 1 demonstrates the relationship between protein-creatinine ratio and 24-hour protein excretion. The Spearman correlation coefficient between 24-hour protein excretion and random urine protein-creatinine ratio was 0.56 (P < .01). When patients with a creatinine level of 1 mg/dL or greater were excluded, the correlation coefficient was the same (0.56, P < .01). The associations of maternal age and gestational age at collection with protein-creatinine ratio and 24-hour protein excretion were not significant (–0.05, P = .5; –0.01, P = .9, respectively).

View larger version (19K): [in this window] [in a new window]   Fig. 1. Relation between 24-hour protein excretion and random urine protein-creatinine ratio. Al. Protein-Creatinine Ratio in Pregnancy. Obstet Gynecol 2004.

The receiver operating characteristic curve for the random urine protein-creatinine ratio is shown in Figure 2. The area under the receiver operating characteristic curve is 0.86 (95% confidence interval 0.80–0.93; P < .001). Sensitivity, specificity, and predictive values for various cutoffs are shown in Table 2. A cutoff point that yields 100% specificity is not available. At a cutoff protein-creatinine ratio of 0.19 for detection of significant proteinuria, sensitivity was 85%, with a false positive rate (1-specificity) of 27%. With this cutoff, the positive predictive value was 46% and negative predictive value was 95%. There were 6 false negative and 39 false positive test results. With this cutoff, 39% of patients had a positive test result. The patients with false negative test results had protein levels between 0.5 g and 3.0 g on 24-hour protein collection. The cutoff point that maximized both sensitivity and specificity of protein/creatinine ratio for significant proteinuria on 24-hour urine collection was 0.49 (Table 2).

View larger version (17K): [in this window] [in a new window]   Fig. 2. Receiver operating characteristic curve for various cutoffs for the random urinary protein-creatinine ratio as a predictor of significant proteinuria (area under receiver operating characteristic curve = 0.86 [95% confidence interval 0.80–0.93], P < .001). Al. Protein-Creatinine Ratio in Pregnancy. Obstet Gynecol 2004.

	DISCUSSION

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In most previous studies, it has been reported that random urine protein-creatinine ratio is well correlated to 24-hour protein excretion in patients with hypertensive disorders of pregnancy.^2–8 Interpretation of a test, however, varies by prior probability of the disease. In the present study, we primarily investigated the ratio of significant proteinuria in a group of consecutive patients who had new-onset mild hypertension in late pregnancy. The data included only 3 patients with proteinuria of 5 g or greater on 24-hour urine collection, and we were able to assess the validity of random urine protein-creatinine ratio for mild gestational hypertension and mild preeclampsia.

In the present study, the adequacy of 24-hour urine specimens was ensured by excluding those containing less than 10 mg creatinine/kg per day. The percentage of patients with significant proteinuria was 21%. We did not estimate a cutoff point that yields 100% sensitivity. The negative predictive value of random urine protein-creatinine ratio was high and did not vary greatly with an increasing cutoff point of protein-creatinine ratio for significant proteinuria detection. We chose a cutoff point (> 0.19) that minimized the false positive ratio while maintaining high sensitivity. With use of this cutoff point, the test had a good negative predictive value (95%) in excluding significant proteinuria. However, the positive predictive value of the test was only 46%, and a test result above the cutoff point was not diagnostic for significant proteinuria.

The random protein-creatinine ratio can be used in serial testing with 24-hour urine collection in mild hypertensive disorders of pregnancy. For a patient with a positive random urinary protein-to-creatinine ratio, proceeding with collection of a 24-hour urine sample seems a reasonable option. In the current study, with use of a cutoff greater than 0.19, 39% of the patients had a positive test result. With serial testing, 61% of the patients would be excluded from 24-hour urine collection. Six patients had false negative results, and the 24-hour protein excretion of these patients showed a wide variation. Patient management decision making is a complex process, and it is difficult to suggest the overall impact of a false negative test on the prognosis of pregnancy. However, the impact would be limited in a patient who has no indications of severe disease.

The diagnostic accuracy of the protein/creatinine ratio in the prediction of proteinuria was investigated in 2 recent studies.^2,10 A high negative predictive value is available in both studies for patients with a low prior probability of disease. With a cutoff of 0.19 or greater, Rodriguez-Thompson and Lieberman² reported a sensitivity of 90% and a specificity of 70%. Durnwald and Mercer¹⁰ reported a sensitivity of 91% and specificity of 48% with a cutoff point of 0.20. Using Bayes’ theorem, given a prior probability of 21% for significant proteinuria, a negative predictive value of 97% was estimated from the study of Rodriguez-Thompson and 95% from that of Durnwald and Mercer.

We estimate a moderate correlation between random protein-creatinine ratio and 24-hour protein excretion. In the study of Durnwald and Mercer,¹⁰ in which in 89% of cases underwent 24-urine collection by means of a Foley catheter, a poor correlation was reported between random protein-creatinine ratio and 24-hour protein excretion and between random protein-creatinine and the protein-creatinine ratio from 24-hour urine.¹⁰ In their novel study, Ginsberg et al¹ proposed that random urine protein-creatinine ratio provides a good estimation of total protein excretion per 24 hours, when glomerular filtration was stable and urinary creatinine and protein excretion was assumed to be fairly constant. Then, the 24-hour protein excretion rate could be estimated by the concurrent rate of creatinine excretion. Their study did not include pregnant women. Protein excretion rates, however, can vary from hour to hour in preeclampsia.^14,15 Chesley reported up to 5-fold variation of protein excretion in 4 hourly collections.¹⁴ Therefore, a random protein-creatinine ratio may not reflect adequately 24-hour protein excretion.

In conclusion, random urine protein-creatinine ratio is a poor predictor of significant proteinuria in new-onset mild hypertensive disorder of pregnancy and should not replace the 24-hour urine collection as a diagnostic test. It accurately excludes significant proteinuria and may be useful for ruling out preeclampsia.

	Footnotes

 
Received January 15, 2004. Received in revised form May 1, 2004. Accepted May 21, 2004.

10.1097/01.AOG.0000134788.01016.2a

	REFERENCES

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11. Johnson AM, Rahlfs EM, Silverman LM. Proteins. In: Burtis CA, Ashwood ER, Tietz NW, editors. Tietz textbook of clinical chemistry. Philadelphia (PA): W. B. Saunders; 1999. p. 477–540.

12. Newman DJ, Price CP. Renal function and nitrogen metabolites. In: Burtis CA, Ashwood ER, Tietz NW, editors. Tietz textbook of clinical chemistry. Philadelphia (PA): W. B. Saunders; 1999. p. 1204–70.

13. Zhou X-H, Obuchowski NA, McClish DK. Estimation and hypothesis testing in a single sample. In: Statistical methods in diagnostic medicine. New York (NY): Wiley-Interscience; 2002. p. 100–64.

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