Predicting proteinuria in hypertensive pregnancies with urinary protein-creatinine or calcium-creatinine ratio

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1 (2007) 27, r 2007 Nature Publishing Group All rights reserved /07 $30 ORIGINAL ARTICLE Predicting proteinuria in hypertensive pregnancies with urinary protein-creatinine or calcium-creatinine ratio DEE Rizk 1, MM Agarwal 2, JY Pathan 3 and EN Obineche 3 1 Department of Obstetrics and Gynecology, United Arab Emirates University, Al-Ain, UAE; 2 Department of Pathology, United Arab Emirates University, Al-Ain, UAE and 3 Department of Internal Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, UAE Objective: Evaluate the value of random urinary protein-creatinine (PrCr) and calcium-creatinine (CaCr) ratios to predict 24-h proteinuria in hypertensive pregnancies. Study Design: Spot urine samples were collected before routine 24-h urine collections from consecutive pregnant women with hypertension (n ¼ 83). Reliability of spot urinary PrCr and CaCr to detect significant proteinuria (X300 mg/day) using 24-h urine protein as gold-standard was assessed by receiver-operating characteristic (ROC) curve. Results: Fifty-one patients (61.4%) had significant proteinuria (45 preeclampsia, 5 superimposed pre-eclampsia, 1 renal hypertension). Area under ROC curve to predict proteinuria was 0.82 (95% confidence interval (CI) 0.73 to 0.92, P<0.001) for PrCr and 0.55 (95% CI 0.43 to 0.68, P ¼ 0.2) for CaCr. A cutoff value of >0.19 for PrCr best predicted significant proteinuria with sensitivity, specificity, positive and negative predictive values and likelihood ratios (positive and negative), respectively, of 80.4, 68.8, 80.4, 68.8%, 2.57 and Conclusion: Spot urinary PrCr predicts total urinary protein excretion in hypertensive pregnancies. (2007) 27, doi: /sj.jp Keywords: hypertension; pregnancy; proteinuria; urinary calciumcreatinine ratio; urinary protein-creatinine ratio Introduction Hypertensive disorders of pregnancy (HDP) are one of the most common medical complications of pregnancy globally accounting for much maternal and perinatal morbidity and mortality. 1 6 Detecting and quantifying proteinuria is an integral part for both the diagnosis and assessment of severity of these disorders. The presence of significant proteinuria (>300 mg/day) is associated with higher maternal and fetal risks among hypertensive Correspondence: Dr DEE Rizk, Department of Obstetrics and Gynecology, Faculty of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al-Ain, United Arab Emirates. rizk.diaa@uaeu.ac.ae Received 13 September 2006; revised 14 December 2006; accepted 6 February 2007 pregnancies. 1,4 9 The amount of proteinuria is also directly related to the likelihood of obstetric complications. 5 8,10 However, the methods of reporting the presence or extent of proteinuria in hypertensive pregnancies are poorly described and standardized. 1,8 Detection of proteinuria in hypertensive pregnant women is usually done by routine simple visual dipstick urinalysis of a voided midstream sample. 1,7,8,11,12 Recent studies have, however, shown that this method is inaccurate with high false-positive and negative-results when compared to the gold standard of 24-h urine protein measurement. 1,2,6 8,10,12,13 The latter measurement is also traditionally used for quantifying proteinuria in hypertensive pregnant women but has several limitations. 1 3,6 9,11 18 Most importantly, the laboratory results are not available to the clinician before 24 h, which may delay the ideal strategy for the immediate management of hypertension during pregnancy. The use of a spot urine protein-creatinine or calcium-creatinine excretion could provide a simpler, quicker, more convenient and less expensive alternative assessment of the presence and/or subsequent 24-h amount of proteinuria in hypertensive pregnant women. The accuracy of these investigations has been described in most studies of hypertensive and healthy pregnant women, 1,3,5 7,11,15 21 as well as nonpregnant healthy volunteers and patients with renal impairment. 15,17,18,22 These simple urine tests could assist in improving the clinical triage of hypertensive pregnant women with a potential for decreasing the workload of the maternity staff. It would also reduce the demand and cost of laboratory services particularly in resource-constrained settings, like our own, where HDP are particularly prevalent. 5,6,8,17,18,21 23 The aim of our study, therefore, was to evaluate the value of random urinary protein-creatinine and calcium-creatinine concentration in a consecutive sample of women with HDP in predicting 24-h proteinuria in our institution. Materials and methods A prospective cohort study was conducted on all consecutive pregnant women with HDP admitted to the antenatal ward of

2 Urinary protein-creatinine and proteinuria 273 Al-Ain Hospital (Al-Ain, United Arab Emirates (UAE)) for management of hypertension from 1 November, 2005 to 28 February, The hospital is one of the two teaching hospitals affiliated with the Faculty of Medicine and Health Sciences (UAE University), and one of the two main maternity units in Al-Ain city that provides tertiary obstetric services to a multi-ethnic group of women. The study protocol was approved by the Research Ethics Committee of the Faculty. There are between 3000 and 3500 deliveries per year in the hospital. Sample size calculation indicated that a study of 95 subjects was adequate to achieve a high degree of precision (95% confidence interval (CI) of 10%) in estimating the accuracy of random urinary protein-creatinine and protein-calcium ratios as diagnostic tests for significant proteinuria in patients with HDP. 24 Of interest were systematic differences between the spot tests and the gold standard and the correlation between the two. Our a priori intention was to detect a systematic difference between the spot urine tests and the gold standard 24-h urine protein as diagnostic tests for significant proteinuria in patients with HDP, with a 90% power and 5% significance level, of one-third the standard deviation of the difference. The Fisher z-transformation of the correlation coefficient between the spot tests and gold standard, with this sample size, can be estimated with a standard error of approximately Thus if the estimated correlation coefficient is 0.8, we will obtain a 95% confidence interval of (0.72, 0.87) which is sufficiently precise. As the background prevalence of HDP in the hospital pregnant population is approximately 5% (Annual perinatal statistics, 2004), it was also calculated that this population of women (n ¼ 95) was equivalent to 25% of the expected annual hospital inpatient volume of pregnant women with HDP and would thus provide an adequate and representative sample of the institutional database. Standard terminology of the American College of Obstetricians and Gynecologists was used for the diagnosis and classification of HDP. 4 Hypertension during pregnancy was thus defined as a sustained blood pressure increase of 140 mm Hg systolic or 90 mm Hg diastolic after 20-weeks gestation recorded in a uniform manner using a standard sphygmomanometer with the fourth Korotkoff sound determining the diastolic blood pressure. Significant proteinuria during pregnancy was considered as urine protein excretion exceeding 300 mg/day (24 h). Women with intrauterine fetal death, coexisting or recurrent urinary tract infection and current diuretic therapy within 7 days of the hospital visit and immuno-compromised patients were excluded from the study. Subjects who have been placed on long-term bed rest at home or strict bed rest in another hospital for more than 36 h before admission were also excluded because of the decreased correlation between the urine protein-creatine ratio and the 24-h urine protein resulting from prolonged recumbency. 2,6,8,16,17 All eligible subjects (n ¼ 95) received written information before enrollment and 90 agreed to enter the study. A spot clean-catch and midstream voided urine sample was collected from each patient for measurement of protein, creatinine and calcium immediately before routine 24-h urine collection. This was ordered for measuring the 24-h urine protein excretion as part of the institution s standard workup of women with HDP and was usually started at 0800 on the morning following admission. Some patients were ambulatory ad libitum, but were instructed to remain in the left lateral decubitus position when recumbent during the 24-h collection to avoid ureteral compression and inadequate collection. 5,18 Adequate 24-h collections were further defined as those containing at least 10 mg creatinine/kg pre-pregnancy weight in 24 h. 9,15,18 None of the spot samples was first-voided morning urine because of the diminished reliability of this specimen for measuring protein-creatinine ratio as a result of prolonged recumbency overnight. 6,14,16 Maternal demographic, obstetric and medical variables were abstracted from the case notes. All specimens were transported to the laboratory within 1 h for subsequent analysis to avoid potential errors of measurement after prolonged storage of urine. 8,18,22 The urine protein, creatinine and calcium concentrations were measured by a standard technique using the Beckman Synchron (Beckman-Coulter Instruments, Brea, CA, USA). The overall coefficient of variation of day-to-day imprecision for creatinine, calcium and urinary protein was 3.3, 3.2 and 1.2%, respectively. The hospital laboratory subscribes to an overseas external quality control from the United Kingdom (UK National External Quality Assessment Scheme). The average deviation of creatinine, calcium and urinary protein from the target mean (for 6 months, June December, 2005) was 3.4, 3.2 and 3.4%, respectively. The urine protein-creatinine and calciumcreatinine ratios were obtained by dividing the urine protein and calcium concentrations by the creatinine concentration in mg/dl. The individual results of spot urinary assays were not made available to the obstetricians responsible for patient care and thus did not influence the clinical management of HDP during the study period. 5,20 Similarly, this information was not available to the investigators performing the laboratory measurements and therefore did not bias the judgment about the results. 20 Data were analyzed using the Statistical Package for the Social Sciences (SPSS Inc., version 12; Chicago, ILL, USA.). All measurements were presented as mean±standard deviation (s.d.) in mg/dl as the data had a normal distribution. The area (AUC) under the receiver-operating characteristic (ROC) curve was used to analyze the performance of the protein-creatinine and calciumcreatinine ratios to predict proteinuria. To measure test performance, specific thresholds were reviewed individually with the sensitivity, specificity, positive and negative predictive values for different threshold values of protein-creatinine and calciumcreatinine ratios along with likelihood ratios of positive and negative tests using standard definitions. For all analyses, a P<0.05 was considered significant.

3 274 Urinary protein-creatinine and proteinuria Results Eighty-three of the 95 recruited women with HDP (87.4%) participated in the study. Five women declined to participate and seven more subjects were excluded after enrollment because of inadequate 24-h collections defined as those containing <10 mg creatinine/kg pre-pregnancy weight in 24 h. No further data were available on these 12 women. None of the study subjects (n ¼ 83) was on restricted salt diet, was taking medication except iron and vitamin supplements and a-methyl dopa and/or insulin and has received intravenous infusion before urinalysis. The overall prevalence of HDP during the study period was 5.3% (95/1780). The majority of study patients (76/83, 91.5%) had their previous antenatal care in the hospital, whereas the rest (7/83, 8.5%) were referred from elsewhere. Table 1 describes other patient demographics including the important obstetric and medical factors. The study sample was representative of the hospital s obstetric case mix and of the general female population. 23 Fiftyfour participants (65.1%) were primigravidas and 29 (34.9%) were Table 1 Characteristics of study population (N ¼ 83) Age (years) 29.4±6.6 (16 45) a Parity 2.1±1.9 (1 8) Maternal body mass index at 26.1±9.6 ( ) sampling (kg/m 2 ) Gestational age at sampling 32.1±1.6 (22 38) (weeks) Nationality 1 Arab 46 (55.4) b 2 Indian/Pakistani 26 (31.3) 3 United Arab Emirates 10 (12.1) 4 Filipino 1 (1.2) Blood pressure at sampling (systolic/diastolic in mm Hg) 153.3±12.9 ( )/ 97.2±8.2 (90 110) Medical history 1 gestational diabetes 15 (18.1) mellitus 2 anemia (hemoglobin 3 (3.6) <11g/dl) 3 asthmatic bronchitis 1 (1.2) Classification of hypertension 1 pre-eclampsia 44 (53) 2 gestational hypertension 29 (34.9) 3 superimposed 5 (6.1) preeclampsia 4 chronic hypertension 4 (4.8) 5 renal hypertension 1 (1.2) Abbreviatioon: s.d., standard deviation. a Mean±s.d. (range). b Number (percentage). multigravidas. Five women had twin pregnancy (6%), whereas the rest were singleton pregnancies. The majority of patients with HDP (n ¼ 51, 61.4%) had significant proteinuria (X300 mg/day), 45 had pre-eclampsia, five had superimposed pre-eclampsia and one had renal hypertension. Four of these women (4.8%) had severe HDP (proteinuria >5g/day), three developed further obstetric complications necessitating early delivery and one delivered near term. No patient developed eclampsia. The majority of hypertensive women (n ¼ 63, 75.9%) were already treated at enrollment with oral a-methyl dopa 1 2 g/day without further drug combination. Adequate urine collection (>10 mg creatinine/kg pre-pregnancy weight in 24 h) was confirmed in 83 of the 90 specimens of 24-h urine. The mean±s.d. 24-h urinary protein excretion and creatinine concentration in study subjects were ±186.2 mg (range 65 to mg) and 78.5±45.6 mg/dl (range 21.7 to mg/dl), respectively. The sensitivity, specificity and positive and negative predictive values and likelihood ratios of spot urinary protein-creatinine ratio for significant proteinuria at different cutoff levels are shown in Table 2. A cutoff value of >0.19 gave the best prediction with an AUC of 0.82 (95% CI 0.72 to 0.91, P<0.001), as depicted in Figure 1. The sensitivity, specificity and positive and negative predictive values and likelihood ratios of spot urinary calcium-creatinine ratio for significant proteinuria are shown in Table 3. The AUC was 0.55 (95% CI 0.43 to 0.69, P ¼ 0.2). Discussion This study shows the value of measuring spot random urinary protein-creatinine and calcium-creatinine ratios in predicting 24-h urinary protein excretion in a hospitalized pregnant population with HDP. 17 Our study also stresses the need for more frequent audit of the operational policies of laboratory and obstetric hospital services and for regular update of patient management protocols in resource-constrained settings in the developing world. 5,8 The results clearly showed that spot urinary protein-creatinine in a pre-24 h urine collection sample is predictive of total urinary protein excretion in hospitalized pregnant women with HDP irrespective of the amount of proteinuria or type of hypertension. This random urine test is thus useful to assess 24-h urinary protein excretion and is faster, less expensive and more convenient measurement that can be easily performed in daily clinical practice. This allows more timely, cost-effective and less labor-intensive therapeutic intervention in pregnant women with severe hypertension. 5,6,8,17,18,21 Comparison of results from various studies estimating the accuracy of spot urinary protein-creatinine ratio in predicting total 24-h urine protein excretion in women with HDP is, however, limited by differences in the prevalence and definition of HDP particularly the classification, onset and severity. 4,19,20 Other factors are definition of significant proteinuria (protein excretion

4 Urinary protein-creatinine and proteinuria 275 Table 2 Performance of spot urinary protein-creatinine ratio (best cutoff value and above) compared to 24-h urinary protein excretion in detection of significant proteinuria (>300 mg/day) Threshold PrCr ratio > Number of patients >threshold (TP±FP) % Patients >threshold Number of patients <threshold (TN+FN) Sensitivity (%) Specificity (%) PPV (%) NPV (%) LR LR Abbreviations: PrCr, protein-creatinine; TP, true positive; TN, true negative; FP, false positive; FN, false negative; PPV, positive predictive value; NPP, negative predictive value; LR+, positive likelihood ratio; LR, negative likelihood ratio. Sensitivity CaCr ratio PrCr ratio Specificity Figure 1 ROC analysis showing the performance of spot urinary protein-creatinine (PrCr) or calcium-creatinine (CaCr) ratio for significant proteinuria (>300 mg/day). >300 mg/24 h or lower threshold) and type of pregnant patient populations studied (ambulatory or hospital-based and whether they were hypertensive or not), the ethnic group examined, the laboratory methods used for measurements including urine sampling techniques and standards and methods of urine collection. 5,6,8,12,17,18,21,22,25 Therefore, available results vary widely but comparable studies of hypertensive pregnant women belonging to the same age and parity spectrum have reported positive and negative predictive values for spot urinary protein-creatinine ratio between 46 and 95% and 45 and 98%, respectively, with positive and negative likelihood ratios between 1.8 and 16.5 and 0.06 and 0.35, respectively, and a cumulative correlation coefficient of >0.9 for 24-h urinary protein excretion. 17 This is in agreement with the overall results observed in our study. The cutoff value of spot urinary protein-creatinine ratio that gave the best prediction for Table 3 Performance of spot urinary calcium-creatinine ratio compared to 24-hour urinary protein excretion in detection of significant proteinuria (>300 mg/day) Threshold CaCr ratio > Number of patients >threshold (TP+FP) % Patients >threshold Number of patients <threshold (TN+FN) Sensitivity (%) Specificity (%) PPV (%) NPV (%) LR LR Abbreviations: CaCr, calcium-creatinine; TP, true positive; TN, true negative; FP, false positive; FN, false negative; PPV, positive predictive value; NPP, negative predictive value; LR+, positive likelihood ratio; LR, negative likelihood ratio. significant proteinuria in our study (>0.19) was also similar to some previous studies. 3,9,11 Random urinary protein-creatinine ratio provides some evidence to rule out the presence of significant proteinuria in women with HDP as defined by a 24-h urine excretion measurement with a cumulative negative likelihood ratio of 0.14 (95% CI 0.09 to 0.24). 17 The higher negative likelihood ratio of 0.35 reported in the present study could be explained by the higher prevalence of HDP in our setting, 23 as this ratio is directly proportional to the prevalence of the disease in the population under study. 5,6,9,11 24-h urinary protein concentration is the gold standard measurement used for quantifying proteinuria in women with HDP but has several logistic and clinical disadvantages especially when the patients are not hospitalized. 1 3,6 9,11 18,25 These include inaccurate timing or incomplete collection of 24-h urine as result of potential effects of posture, lack of compliance and increased ureteral dead space in pregnancy, inconvenience to patients and nursing staff and cumbersome, time-consuming and expensive process of laboratory measurements. Protein excretion in urine is also affected by several factors such as variations in water intake and excretion, rate of diuresis, timing of urine collection, exercise, diet and posture being greater in the standing than in the supine position. 2,5,6,8,12,14,16 18,20 22,25 Our study population was hospitalized and nonambulatory and therefore, our results cannot be extrapolated to ambulatory pregnant women with hypertension. 6,16 The usefulness of the random urinary proteincreatinine ratio for the diagnosis of severe HDP (proteinuria >5g/day) in our sample was also limited because there were only four patients with such condition, similar to other studies. 11,14 The accuracy of this test, however, was independent of the degree of proteinuria in some, 11,16 but not all 3,9,13 studies. It is possible that in the second and third trimester of pregnancy when HDP are diagnosed, the urinary protein-creatinine ratio may not predict

5 276 Urinary protein-creatinine and proteinuria total urinary protein reliably because of the physiological hemodynamic changes that normally occur during this period of gestation. 26 The relationship between urinary protein-creatinine ratio and urinary protein excretion rate could also be modified by the concurrent rate of creatinine excretion which is positively related to muscle mass. 12,26 There was no significant correlation in our patients, however, between gestational age and maternal weight at sampling and urinary protein-creatinine ratio (r ¼ 0.11, 0.23, respectively), as previously observed. 3 Some studies have also reported a significant diurnal variation in urinary proteincreatinine ratio in hypertensive patients 9,13 In pregnant women whether hypertensive or normotensive, the single voided urine sample protein-creatinine ratio, however, is strongly correlated with 24-h proteinuria irrespective of the sampling time or nonresting situation in contrast to nonpregnant women. 21,25 Therefore, a voided urine sample obtained on arrival at the clinic in patients with HDP is reliable for measurement of urinary protein-creatinine ratio and in retrospect could have circumvented the need for obtaining a post first-voided morning urine sample after admission to the hospital in our study. 21 On the basis of the fact that urinary calcium excretion decreases in HDP, measurement of spot urinary calcium-creatinine ratio had been studied for early prediction of HDP particularly pre-eclampsia with conflicting results. 19,20 The use of this test to predict total urinary protein excretion in patients with HDP as described in this study, however, has not previously been reported. The predictive accuracy of spot urinary calcium-creatinine ratio for significant proteinuria was very poor and in fact very close to the lowest recommended statistical threshold for a useful test (AUC of 0.5) in our study. Therefore, the clinical usefulness of this measurement as an alternative or supplement to spot urinary protein-creatinine ratio in hypertensive pregnant women is limited. In conclusion, spot urinary protein-creatinine ratio in hospitalized women with hypertensive disorders of pregnancy is a simple, accurate and convenient measurement that is predictive of subsequent total urinary protein excretion. A ratio of >0.19 gives the best results and therefore can be used as a rapid alternative assessment for the diagnosis and follow-up of the hypertensive pregnant population. References 1 Waugh JJ, Clark TJ, Divakaran TG, Khan KS, Kilby MD. Accuracy of urinalysis dipstick techniques in predicting significant proteinuria in pregnancy. 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6 Urinary protein-creatinine and proteinuria Tsujikawa H, Machii R, Hiratsuka N, Shiba K, Fukuta H, Sakamoto H et al. Evaluation of novel test strip to measure albumin and creatinine in urine. Jpn J Clin Pathol 2005; 53: Rizk DEE, Nasser M, Thomas L, Ezimokhai M. Women s perceptions and experiences of childbirth in United Arab Emirates. J Perinat Med 2001; 29: Snedecor GW, Cochran WG. Statistical Methods. 8th edn. Iowa: Iowa State University Press, 1989; Gaspari F, Perico N, Remuzzi G. Timed urine collections are not needed to measure urine protein excretion in clinical practice. Am J Kidney Dis 2006; 47: Haas DM, Sabi F, McNamara M, Rivera-Alsina M. Comparing ambulatory spot urine protein/creatinine ratios and 24-h urine protein measurements in normal pregnancies. J Matern Fetal Neonatal Med 2003; 14: