Original Article Random Urine Protein/Creatinine Ratio as a Predictor of Significant Proteinuria

Nigam Ankita1, Arora Renu2, Kaur Charanjeet3

To cite: ** ** Received on:

Accepted on:

Source of Support: Nil Conflict of Interest: Nil

ABSTRACT Background: Proteinuria is a major component of preeclampsia. Urine protein measurement after 24-hour urine collection is the traditional standard method for the detection of proteinuria. It is time consuming and is associated with collection errors. As an alternative, random spot sampling for a urine protein / creatinine (P/C) ratio has been investigated. AIM: We carried out this study to compare the two rapid methods of protein estimation: dipstick method and spot urine protein / creatinine ratio (UPCR) with that of 24-h urine protein in patients of preeclampsia for prediction of significant proteinuria. Study Design: Prospective cross-sectional study Method: Two hundred women who fulfilled the criteria of preeclampsia were included in the study. The values of proteinuria estimated by dipstick method and spot UPCR were compared with that of 24-h urine protein. The strength of correlation was measured by Pearson’s correlation coefficient (r). A p value of < 0.05 is considered to be statistically significant. The most discriminant spot UPCR value for detecting significant proteinuria (≥300 mg/day) was determined by plotting receiver–operator curve (ROC). Result: The value of spot UPCR strongly correlated with 24-h urine protein (r = 0.857 with p value < 0.001). The most discriminant spot UPCR value for detecting significant proteinuria (≥300 mg/day) was 1.16. Area under ROC for spot UPCR (0.96) was significantly more than that for dipstick urine analysis (0.766), making spot UPCR the better predictor of significant proteinuria. Spot UPCR also came out to be better predictor of adverse feto-maternal outcome. Conclusion: Spot UPCR can be used as a rapid and reliable alternative method in preference to 24-h proteinuria in patients of preeclampsia. Also spot UPCR can be used to predict the risk of adverse feto-maternal outcome of the pregnancy. Keywords: Preeclampsia, spot UPCR, 24 hr. proteinuria, dipstick urinanalysis.

INTRODUCTION dipstick 1+ Or (in absence of proteinuria) evidence of multisystem involvement like thrombocytopenia Preeclampsia, as mild or severe disease is responsible (platelets < 1,00,000/µl), or renal insufficiency, for most of the hypertensive disease observed during S.Creatinine> 1.1 mg/dL or doubling of baseline pregnancy. Preeclampsia is defined as the presence (no prior renal disease),or liver involvement (Serum of BP ≥ 140/90 mmHg after 20 weeks in previously transaminase levels twice normal AST or ALT), or normotensive women, and proteinuria ≥ 300mg/24 cerebral symptoms - headache, visual disturbances, hr, or urine protein-creatinine ratio ≥ 0.3, or persistent

Pan Asian Journal of Obstetrics and Gynecology, May–Aug 2018, Vol 1, Issue 1, (page 5-9) 5

2.indd 5 17-07-2018 22:52:59 Nigam Ankita, et al.

convulsions; or pulmonary edema.1 Detecting midstream urine sample was obtained for measurement proteinuria is an integral part of the management of protein: creatinine ratio during the 24-h collection. of hypertensive pregnant women as its presence is This volume was later adjusted by dilution to make up associated with higher rate of maternal and fetal a total volume of 24-h urine. complication.2,3 Traditionally, performing 24 hr urine Urine protein/creatinine ratio was estimated on Fully collection for total protein has been practised as the Automated Adiva 2400 Chemical Analyser manufactured gold standard method.4 by Siemens, using commercially available kits. Though a reliable indicator of proteinuria, it has The statistical tests used for analysis were Pearson’s the disadvantages of being a cumbersome &time correlation coefficient-expressed as ‘‘r,’’, and student consuming process, subject to collection errors, Chi square test expressed as.χ2 A p value of < 0.05 was requires storage at 4°C or a preservative & demands considered to be statistically significant. strict patient compliance. These drawbacks have necessitated the use of a rapid method for diagnosing RESULTS significant proteinuria that could help us make more 200 patients of preeclampsia with gestational age timely decisions regarding delivery and the use of ≥24 weeks were included in the study. The general magnesium sulphate for seizure prophylaxis. characteristics of patients are mentioned in Table 1. The We carried out this study to compare the diagnostic mean age of the patients was 27.3 ± 2.6 years. Majority accuracy of dipstick urinanalysis and random urine of the patients were nulliparous with mean gestational protein-creatinine ratio in assessment of significant age of 36.5 ± 2.7 weeks. Early onset preeclampsia (< 34 proteinuria in pregnant females with hypertension. weeks) was seen in 1/5th of the study population. 57.50% had signs and symptoms of impending eclampsia and MATERIAL AND METHODS almost one third of the patients had severe hypertension We carried out this prospective cross-sectional study on admission. Significant proteinuria was seen in 77.5% was conducted in the Department of Obstetrics and of the study population. The mean 24 hr urine protein Gynaecology in collaboration with the department of was 1704.39 ± 1338.94 mg/24 h. Biochemistry in Vardhman mahavir medical college The quantitative value of proteinuria estimated by & Safdarjung hospital, New Delhi. Two hundred spot UPCR and its correlation with 24-h proteinuria pregnant women with gestational age ≥24 weeks and is given in Table 2. The maximum number of cases (56 ≤ 40 weeks who were admitted in the maternity ward with hypertension (BP ≥ 140/90), between June 2015 to Table 1 February 2017 were enrolled. The study was approved by General characteristics of patients

ethical committee of the Hospital and informed consent Sr. No. Parameter (n=200) Value was taken before enrolling patients. Women with 1 Mean age in years (SD) 27.3 (2.6) chronic hypertension, diabetes mellitus, pre-existing 2 Nulliparous (%) 46 renal disease, UTI, prolonged foley’s catheterization 3 Mean POG at diagnosis in weeks 36.5 (2.7) (>24 hrs), multiple gestations, premature rupture of (SD) membrane and post term pregnancy were excluded 4 Women with S/S of impending from the study. eclampsia At the time of admission, random urine was tested 5 Diastolic BP at admission (%) 38 for protein by the semi-quantitative dipstick method • 90-99 mm Hg 35 using the commercially available SD Urocolor dipstick. • 100-109 mm Hg Results were read according to the color scale provided. • ≥ 110 mm Hg 27 The first voided morning urine specimen was discarded, 6 Women with significant proteinuria 77.5 and the patients were instructed to rest at least for 1 h in (%) left lateral decubitus to avoid ureteral compression. The 7 Mean 24 hr urine protein (mg/24hr) 1704.39 24-h urine collectionwas done till the first voided urine (SD) (1338.94) specimen of the next morning. 5–10 ml of the voided 8 Mean spot U P/C ratio (SD) 1.96 (1.54)

6

2.indd 6 17-07-2018 22:53:00 Random Urine Protein/Creatinine Ratio as a Predictor of Significant Proteinuria

Table 2 Correlation of spot urine P/C ratio with 24 hr urine protein

UP/CR N 24 HR. PROTEIN (mg/24hr) Correlation Coefficient P Value Mean Range (r) <0.3 41 326.4 ± 377 39.5-1802.4 0.214 P > 0.05 (0.180) 0.3-2.99 108 1560 ± 707 50.25- 2956 0.851 P < 0.00l ≥3.0 51 3116.7 ± 1620 1095.6 - 6830 0.097 P > 0.05 (0.496) OVERALL CORRELATION COEFFICIENT FOR 200 CASES=0.857 AT P VALUE<0.001

Table 3 Correlation of urine albumin (dipstick) with 24 hour Table 4 Comparison of different cut-off values of spot urine proteinuria P/C ratio in prediction of significant proteinuria

Urine albu- 24 hr. U. Pr. (mg/ 24 hr) P value Cut-off Sn (%) 95% CI Sp(%) 95% CI min (dipstick) < 300 ≥ 300 value TRACE 14 6 <0.0001 0.1 100 97.6- 100 13.33 5.1-26.8 1+ 20 49 0.2 96.13 91.8- 98.6 64.44 48.8-78.1 2+ 10 60 0.3 96.13 91.8- 98.6 80 65.4-90.4 3+ 1 27 0.4 89.68 83.8- 94 88.89 75.9-96.3 4+ 0 13 1 88.39 82.3-93 93.33 81.7-98.6 TOTAL 45 155 1.16 88.39 82.3-93 100 92.1-100 2.07 58.06 49.9- 65.9 100 92.1-100

%) had spot UPCR in the range of 0.3–3.0 mg/mg while 25.50 % had spot UPCR ≥3.0. Only 20.50 % of the cases had spot UPCR <0.3. The mean spot UPCR was 1.96 ± 1.54. A good correlation between 24-h urine protein and spot UPCR was observed for values between 0.3-3.0 mg/mg with p value <0.001 and correlation coefficient r= 0.851, whereas for extreme spot UPCR values of < 0.3 and ≥3.0, there was poor correlation with r = 0.214 and 0.097 respectively and p value of > 0.05. The estimation of proteinuria by dipstick method and its correlation with 24-h proteinuria are given in Table 3. The maximum number of cases (35 %) had 2+ proteinuria by dipstick. Overall, the correlation was poor with r = -0.09.

DETERMINATION OF CUT OFF VALUE Figure 1 Values of spot P/C ratio 0.3- 2.99 mg/mg In the present study, a cut-off value of spot UPCR that predicts significant proteinuria on 24-h urine sample was calculated at different levels of UPCRs (Table 4). predictive values. The 1.16 spot UPCR yielded a positive On the basis of the ROC (Figure 2), the most predictive value of 100 % and a negative predictive value discriminant spot UPCR value for detecting significant of 71.4 %, while maintaining sensitivity and specificity proteinuria (≥300 mg/day) was 1.16, based on defining at 88.4% and 100 %, respectively. the spot UPCR value which gave the best combination Similarly, cut off value was determined for dipstick of sensitivity, specificity, and positive and negative analysis (Table 5). The value which gave the best

Pan Asian Journal of Obstetrics and Gynecology, May–Aug 2018, Vol 1, Issue 1, (page 5-9) 7

2.indd 7 17-07-2018 22:53:00 Nigam Ankita, et al.

Figure 2 ROC of spot UPCR for 24 hr urine protein Figure 3 ROC of dipstick urinanalysis for 24 hr urine protein

Table 5 Comparison of different cut-off values of urine status of females, raised prevalence of metabolic albumin dipstick in prediction of significant proteinuria syndrome, demographic determinants of the hypertensive disease in pregnancy have fairly remained Cut off Sn(%) 95% CI Sp(%) 95% CI point constant. < 1+ 100 97.6 - 100.0 0 0.0 - 7.9 The mean spot urine P/C ratio was 1.96 ± 1.54. Good linear correlation was observed between spot urine ≥ 1+ 96.13 91.8 - 98.6 31.11 18.2 - 46.6 P/C ratio and 24 hour proteinuria, with spearman’s ≥ 2+ 64.52 56.4 - 72.0 75.56 60.5 - 87.1 coefficient of 0.857 with p value of <0.0001, thereby ≥ 3+ 25.81 19.1 - 33.4 97.78 88.2 - 99.9 making the correlation highly significant. However ≥ 4+ 8.39 4.5 - 13.9 100 92.1 - 100.0 at extremes of values, poor correlation was observed, which did not achieve statistical significance. combination of sensitivity, specificity, and positive and The results of the present study are comparable to negative predictive values, was found to be 2+. previous studies,5-14 showing linear positive correlation ROC analysis was done (Figure 3) and area under ROC between spot urine P/C ratio and 24 hour proteinuria, for UPCR was found to be significantly higher than that thus proving the usefulness of the P/C ratio as a for dipstick analysis. screening tool for the evaluation of proteinuria in subjects with suspected preeclampsia, however few DISCUSSION studies15,16 were found to contradict the same. Despite of good linear correlation in various studies, The present study included 200 hypertensive pregnant a single cut-off for spot urine P/C ratio is yet not women, the mean age was 27.3 ± 2.6 years. Maximum determined. Different cut-off values for UP/C ratio have cases (46%) were nulliparous, and the mean gestational been suggested with different results. The cut-off value age was 36.5 ± 2.7 weeks, with early onset preeclampsia of spot UPCR that predicts significant proteinuria in (< 34 weeks) in 1/5th of the study population.In most 24-h urine sample was found to be 1.16. The sensitivity, of the previous studies,5-16 majority of the cases were specificity, PPV and NPV of spot UPCR 1.16 in this primigravidas, or nulliparous similar to the present study were 88.4, 100, 100, and 71.4 % respectively. A study. systematic review of 16 studies demonstrated a range Over almost two decades, despite lifestyle changes, of sensitivity and specificity for the test between 69–96 socio economic development, change in education

8

2.indd 8 17-07-2018 22:53:01 Random Urine Protein/Creatinine Ratio as a Predictor of Significant Proteinuria

% and 41–97%, respectively, whereas the positive and significant proteinuria in preeclampsia.‐ Australian and negative predictive values ranged between 46 and 95 New Zealand journal of obstetrics and gynaecology. 2006;46(6):501-4. 17 and 45 and 98 %, respectively. These variations can 6. Leanos-Miranda A, Marquez-Acosta J, Romero- be due to different settings in terms of ethnicity and Arauz F, Cardenas-Mondragon GM, Rivera-Leaños R, gestational ages of the patients of preeclampsia and Isordia-Salas I, Ulloa-Aguirre A. P/C ratio in random urine samples is a reliable marker of increased necessitates the careful interpretation of results in 24-hour protein excretion in hospitalized women clinical practice. with hypertensive disorders of pregnancy. Clinical The dipstick method failed to show significant Chemistry. 2007;53(9):1623-8. correlation with the gold standard method in the 7. Dwyer BK, Gorman M, Carroll IR, Druzin M. Urinalysis vs urine protein–creatinine ratio to predict significant estimation of proteinuria. Similar results have been proteinuria in pregnancy. Journal of Perinatology. observed in previous literatures.7,9,10,18 2008;28(7):461-7. The present study demonstrates that the spot UPCR 8. Eslamian L, Behnam F, Tehrani ZF, Jamal A, Marsoosi V. Random urine protein creatinine ratio as a preadmission is as good as 24-h urine protein estimation in patients test in hypertensive pregnancies with urinary protein of preeclampsia. The spot UPCR is superior to urinary creatinine ratio. ActaMedicaIranica. 2011;49(2):81. dipstick tests in screening for significant proteinuria in 9. Kumari A, Singh A, Singh R. Evaluation of rapid diagnostic methods of urinary protein estimation in women with preeclampsia. patients of preeclampsia of advanced gestational age. The strength of the present study was its large The Journal of Obstetrics and Gynecology of India. sample size and large number of cases with significant 2013;63(5):306-10. proteinuria. The limitation of this study was that the 10. Amin SV, Illipilla S, Hebbar S, Rai L, Kumar P, Pai MV. Quantifying proteinuria in hypertensive disorders of completeness and adequacy of 24 hour urine collection pregnancy. International journal of hypertension, 2014. could not be proven. 11. Nischintha S, Pallavee P, Ghose S. Correlation between 24-h urine protein, spot urine P/C ratio, and serum uric acid and their association with fetomaternal outcomes CONCLUSION in preeclamptic women. Journal of natural science, biology, and medicine. 2014;5(2):255. Random urine P/C ratio can be taken as a simple,accurate, 12. Pariyaeksut P, Leetheeragul J, Boriboonhirunsarn D. A reliable and convenient replacement for tedious, time correlation between first-void morning urinary protein consuming 24 h urine protein estimation, especially in to creatinine ratio (UPCR) and 24 hours urinary protein in pregnancy with suspected preeclampsia. Thai Journal countries like India where hospitals are flooded with of Obstetrics and Gynaecology. 2014;22(4):173-80. a large number of in-patients. The dipstick method 13. Demirci O, Kumru P, Arınkan A, Ardıç C, Arısoy R, because of its simplicity and cost may be continued to Tozkır E, Tandoğan B, Ayvacı H, Tuğrul AS. Spot P/C ratio be used as initial screening method though not suitable in preeclampsia as an alternative for 24-hour urine protein. Balkan medical journal. 2015;32(1):51. to be used for quantitation of proteinuria. 14. Gökdo¤an S, AslanÇetin B, Yalç›nBahat P, At›flAyd›n A, Akça A. Comparison of protein amount in 24-hour urine and P/C rate in spot urine of preeclamptic pregnant REFERENCES women. Perinatal Journal 2016;24(3):142-6. 1. American College of Obstetricians and Gynecologists. 15. Aggarwal N, Suri V, Soni S, Chopra V, Kohli HS. A Hypertension in pregnancy. Report of the American prospective comparison of random urine protein- College of Obstetricians and Gynecologists’ task force on creatinine ratio vs 24-hour urine protein in women hypertension in pregnancy. Obstetrics and gynecology. with preeclampsia. The Medscape Journal of Medicine. 2013;122(5):1122. 2008;10(4):98. 2. Ferrazzani S, Caruso A, De Carolis S, Martino IV, 16. Durnwald C, Mercer B. A prospective comparison of Mancuso S. Proteinuria and outcome of 444 pregnancies total P/C ratio versus 24-hour urine protein in women complicated by hypertension. American journal of with suspected preeclampsia. American journal of obstetrics and gynecology. 1990;162(2):366-71. obstetrics and gynecology. 2003;189(3):848-52. 3. Brown MA, Buddie ML. The importance of nonproteinuric 17. Yadav BK, Adhikari S, Gyawali P, et al. Use of protein: hypertension in pregnancy. Hypertension in pregnancy. creatinine ratio in a random spot urine sample for 1995;14(1):57-65. predicting significant proteinuria in diabetes mellitus. 4. Rinehart BK, Terrone DA, Larmon JE, Perry KG, Martin Nepal Med Coll J. 2010;12:100-5. RW, Martin JN. A 12-hour urine collection accurately 18. Waugh JJ, Bell SC, Kilby MD, Blackwell CN, Seed P, assesses proteinuria in the hospitalized hypertensive Shennan AH, Halligan AW. Optimal bedside urinalysis gravida. Journal of perinatology. 1999;19(8). for the detection of proteinuria in hypertensive 5. Zadehmodarres S, Razzaghi MR, Habibi G, Najmi pregnancy: a study of diagnostic accuracy. BJOG: An Z, Jam H, Mosaffa N, Kaboosi M. Random urine International Journal of Obstetrics & Gynaecology. protein to creatinine ratio as a diagnostic method of 2005;112(4):412-7.

Pan Asian Journal of Obstetrics and Gynecology, May–Aug 2018, Vol 1, Issue 1, (page 5-9) 9

2.indd 9 17-07-2018 22:53:01