The efficacy of semi-quantitative urine protein-to-creatinine (P/C) ratio for the detection of significant proteinuria in urine specimens in health screening settings
- Chih-Chun Chang†1,
- Ming-Jang Su†1,
- Jung-Li Ho1,
- Yu-Hui Tsai1,
- Wei-Ting Tsai1,
- Shu-Jene Lee1,
- Tzung-Hai Yen2 and
- Fang-Yeh Chu1, 3, 4, 5Email authorView ORCID ID profile
© The Author(s) 2016
Received: 19 May 2016
Accepted: 26 September 2016
Published: 13 October 2016
Urine protein detection could be underestimated using the conventional dipstick method because of variations in urine aliquots. This study aimed to assess the efficacy of the semi-quantitative urine protein-to-creatinine (P/C) ratio compared with other laboratory methods.
Random urine samples were requested from patients undergoing chronic kidney disease screening. Significant proteinuria was determined by the quantitative P/C ratio of at least 150 mg protein/g creatinine. The semi-quantitative P/C ratio, dipstick protein and quantitative protein concentrations were compared and analyzed.
In the 2932 urine aliquots, 156 (5.3 %) urine samples were considered as diluted and 60 (39.2 %) were found as significant proteinuria. The semi-quantitative P/C ratio testing had the best sensitivity (70.0 %) and specificity (95.9 %) as well as the lowest underestimation rate (0.37 %) when compared to other laboratory methods in the study. In the semi-quantitative P/C ratio test, 19 (12.2 %) had positive, 52 (33.3 %) had diluted, and 85 (54.5 %) had negative results. Of those with positive results, 7 (36.8 %) were positive detected by traditional dipstick urine protein test, and 9 (47.4 %) were positive detected by quantitative urine protein test. Additionally, of those with diluted results, 25 (48.1 %) had significant proteinuria, and all were assigned as no significant proteinuria by both tests.
The semi-quantitative urine P/C ratio is clinically applicable based on its better sensitivity and screening ability for significant proteinuria than other laboratory methods, particularly in diluted urine samples. To establish an effective strategy for CKD prevention, urine protein screening with semi-quantitative P/C ratio could be considered.
KeywordsChronic kidney disease Health screening Protein-to-creatinine ratio Proteinuria
The prevalence of chronic kidney disease (CKD) has been increasing worldwide in recent decades. CKD in early stage is characterized by an increased glomerular filtration rate (GFR) with elevated urinary protein excretion. Therefore, protein detection in urine has been widely performed as part of the laboratory diagnosis in early CKD screening. After being diagnosed with early CKD, a patient could be evaluated and treated quickly and appropriately in accordance with current guidelines for CKD (Levey et al. 2007; Stevens and Levin 2013).
The gold standard for measuring urine protein has been 24-h urine protein excretion. Nevertheless, this method is notorious for its inconvenience and the inaccuracy involved in collecting the 24-h urine sample. The most common laboratory test for proteinuria detection is urine dipstick. However, the detection results of urine protein could be underestimated because of the variation in urine samples. The concentration, or dilution due to excessive liquid consumption like water ingestion before the test, is one of the main factors affecting the variation of urine samples. To solve this problem, the urinary creatinine level was measured, and the urine protein-to-creatinine (P/C) ratio was calculated to correct for the variation in urine samples (Pugia et al. 2001; Wallace et al. 2001). The P/C ratio was shown to have acceptable sensitivity and specificity compared with the standard 24-h urine protein testing. Recently, a novel semi-quantitative dipstick test for the urine P/C ratio has become available for efficiently detecting proteinuria (Watanabe et al. 2005; Guy et al. 2009). It was also demonstrated that the urine P/C ratio evaluated by the semi-quantitative method could be practicable and reliable in the health screening for CKD (Wang et al. 2009).
In Taiwan, the government has subsidized regular physical check-ups for people elder than 40 years old, and the exams are annual for individuals older than 65 years and triennial for those aged between 40 and 64 years old. Because of the high prevalence of CKD, urine protein detection was incorporated to identify patients at risk of early stage nephropathy in the physical check-up program. However, the program did not define the optimal laboratory method for detecting proteinuria. As the consequence, the detection rate of significant proteinuria might be different and incomparable between screening centers. Hence, the aim of this study is to evaluate and compare the efficacy of different methods for the detection of significant proteinuria, especially in diluted urine specimens.
A total of 2932 subjects aged at least 40 years and participating in regular physical examinations, subsidized by the National Health Insurance Administration, Ministry of Health and Welfare, Taiwan, were enrolled after the written informed consent were obtained from the participants or one member of their family. Random mid-stream urine was collected for each subject in this study. Urine samples were then sent to Department of Clinical Pathology, Far Eastern Memorial Hospital, for further laboratory analysis. This investigation was approved by the research ethics review committee of Far Eastern Memorial Hospital and was supervised by the data safety monitoring board.
Using the quantitative P/C ratio as the gold standard, the performance of different methods for detecting the existence of significant proteinuria, including traditional semi-quantitative dipstick protein, the new semi-quantitative dipstick P/C ratio, and quantitative urine protein level, was evaluated. Underestimation was defined as the failure of a test to identify significant proteinuria of at least 150 mg protein/g creatinine detected by the standard method of the quantitative P/C ratio. Additionally, urine aliquots with a creatinine concentration of less than 50 mg/dL were regarded as diluted.
Statistical analyses were performed by computing the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and Kappa coefficient of agreement for each laboratory method. The statistical software, SPSS (version 19.0; SPSS Inc., Chicago, USA), was used for all analyses.
Correlation of the urine protein-to-creatinine (P/C) ratio results between the semi-quantitative and quantitative methods
Quantitative P/C ratio (mg protein/g creatinine)
Semi-quantitative P/C ratio (mg protein/g creatinine)
Correlation between the dipstick urine protein and quantitative urine protein-to-creatinine (P/C) ratio results
Quantitative P/C ratio (mg protein/g creatinine)
Correlation between the quantitative urine protein and quantitative urine protein-to-creatinine (P/C) ratio results
Quantitative P/C ratio (mg protein/g creatinine)
Quantitative protein level (mg/dL)
Comparison of the sensitivity, specificity, positive and negative predictive values, Kappa coefficient and rate of underestimation for each laboratory method with the quantitative urine protein-to-creatinine (P/C) ratio
Semi-quantitative P/C ratio (excluding diluted samples)
Semi-quantitative P/C ratio (including diluted samples)
Importantly, we further found that a total of 156 urine samples were considered as diluted, accounting for 5.3 % of the 2932 urine aliquots. Significant proteinuria was found in 60 (39.2 %) of these diluted samples. In the semi-quantitative P/C ratio test, 19 (12.2 %) had positive, 52 (33.3 %) had diluted, and 85 (54.5 %) had negative results. The screening rate of the semi-quantitative P/C ratio test was 45.5 %, including the positive and diluted results. For the 19 subjects with positive results of the semi-quantitative P/C ratio test, 7 (36.8 %) were positive for the traditional dipstick urine protein test, and 9 (47.4 %) were positive for the quantitative urine protein test. Additionally, 52 had diluted results of the semi-quantitative P/C ratio test and 25 (48.1 %) of these subjects had significant proteinuria of at least 150 mg protein/g creatinine. Of these, all were assigned as no significant proteinuria by both traditional dipstick test and quantitative urine protein test.
The prevalence of CKD is increasing, and the condition is becoming a global public health problem. Taiwan is one of countries with high prevalence of CKD. The national prevalence of CKD was estimated to be 11.93 %, and only 3.54 % of patients in Taiwan with CKD were aware of their disorder (Wen et al. 2008). If not diagnosed early and well controlled, CKD might progress into end-stage renal disease (ESRD). Patients with ESRD usually received kidney transplantation or hemodialysis therapy, both of which cost disproportionate amounts in healthcare resources and impaired the quality of life of patients. According to the report of the National Health Insurance Administration, Ministry of Health and Welfare, Taiwan, in 2008, approximately 56,000 people (0.24 % of all people covered by the National Health Insurance) underwent regular dialysis treatment and expended 11 % of the annual healthcare reimbursement. Therefore, it is important for healthy individuals to receive periodic urine screening to prevent the development of incident CKD.
The method for screening for significant proteinuria has not been clearly defined and regulated in Taiwan. The relatively new method of protein detection on a urine dipstick incorporating urine creatinine estimation has been demonstrated to be a more sensitive indicator for detecting significant proteinuria (Xin et al. 2004; Price et al. 2005; Wang et al. 2009; Methven et al. 2010). Distinct from the conventional dipstick test, the semi-quantitative urine P/C ratio possessed an additional advantage for the correction of urine concentration variation by detecting urine creatinine level and, therefore, increased the screening rate of diluted urine samples. In our institution, the abnormal or diluted results of semi-quantitative urine P/C ratio testing for urine samples sent to the laboratory were further interpreted and commented by the clinical pathologist, and were subsequently validated in real time in the outpatient clinic or in the ward. However, the traditional dipstick test remains the most common method used by clinical laboratories for detecting significant proteinuria. As a result, physicians should correlate the clinical manifestations of patients with the urinalysis report carefully because significant proteinuria might be missed because of diluted or underestimated urine samples in such situations. Therefore, it is necessary that the efficacy of each laboratory methods for detecting proteinuria should be compared and analyzed. To the best of our knowledge, our study is the first to describe the underestimated report of urine protein examination for the semi-quantitative P/C ratio, traditional dipstick and quantitative urine protein methods.
The benefits of routine screening for CKD remain controversial, in spite of the increasing prevalence of CKD. Previously, it was suggested that there was no cost-effectiveness of early detection of urine protein for retarding the progression and decreasing the mortality of CKD, unless the urine protein examination was selectively directed toward high-risk groups such as elderly and hypertensive subjects (Boulware et al. 2003). Otherwise, urine protein examinations were recommended to be conducted at an intermission of approximately 10 years in the healthy adult population (Boulware et al. 2003). However, a recent study revealed that universal screening for proteinuria appeared to be an effective strategy for reducing the CKD population because a high positive rate of proteinuria in the general population was shown in Asians, even in persons without hypertension or diabetes (Yamagata et al. 2008). In view of this fact, a more sensitive urine screening tool for proteinuria is necessary, especially for Asian subjects. Besides, the average costs of the quantitative and semi-quantitative urine P/C ratio for a single test in our institution were 2.58 and 2.42 US dollars, respectively. It seems that use of the semi-quantitative urine P/C ratio testing could lead to a minor decrease in cost compared to that of the gold standard testing. The semi-quantitative urine P/C ratio might be a good choice for early detection of proteinuria and appeared to be more effective than the traditional dipstick urine protein test, particularly in diluted urine aliquots.
It is important for physicians to screen for and diagnose CKD based on rapid and accurate urine examinations. Therefore, patients are required to be available for re-collection of urine aliquots for repeated urinalysis, consuming unnecessary laboratory and time costs for further testing confirmation. Considering these factors, patients should be well educated to not consume too much water before urine sample collection because normal or diluted results of the semi-quantitative urine P/C ratio would be present, and falsely negative results could be reported. If this factor is taken into consideration, unnecessary urinalysis retests could be avoided, and timely management could be initiated as needed.
There are some limitations in the present study. First, it was unknown whether subjects undergoing urine protein screening had any underlying diseases such as hypertension or diabetes. Moreover, information regarding racial differences, family history and personal medication use were not available. Additionally, the age of the subjects for proteinuria screening was not included in the exclusion criteria in our study, resulting in some extent of selection bias.
To summarize, the present study indicated that the urine P/C ratio evaluated by a semi-quantitative method is clinically applicable based on its better sensitivity and screening ability for significant proteinuria than other laboratory methods, particularly in diluted urine samples. To establish an effective strategy for CKD prevention in the Asian populations, urine protein screening with semi-quantitative P/C ratio could be considered.
CCC, MJS, THY and FYC conducted study design, statistical analysis, literature review, manuscript preparation and review. JLH, YHT, WTT and SJL performed biochemical analysis, quality assurance, and manuscript review. All authors read and approved the final manuscript.
We thankfully acknowledge the financial support from Far Eastern Memorial Hospital (FEMH-2012-C-057).
The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Boulware LE, Jaar BG, Tarver-Carr ME, Brancati FL, Powe NR (2003) Screening for proteinuria in US adults: a cost-effectiveness analysis. JAMA 290:3101–3114View ArticlePubMedGoogle Scholar
- Guy M, Newall R, Borzomato J, Kalra PA, Price C (2009) Use of a first-line urine protein-to-creatinine ratio strip test on random urines to rule out proteinuria in patients with chronic kidney disease. Nephrol Dial Transplant 24:1189–1193View ArticlePubMedGoogle Scholar
- Levey AS, Atkins R, Coresh J, Cohen EP, Collins AJ, Eckardt KU, Nahas ME, Jaber BL, Jadoul M, Levin A, Powe NR, Rossert J, Wheeler DC, Lameire N, Eknoyan G (2007) Chronic kidney disease as a global public health problem: approaches and initiatives—a position statement from Kidney Disease Improving Global Outcomes. Kidney Int 72:247–259View ArticlePubMedGoogle Scholar
- Methven S, MacGregor MS, Traynor JP, O’Reilly DS, Deighan CJ (2010) Assessing proteinuria in chronic kidney disease: protein–creatinine ratio versus albumin–creatinine ratio. Nephrol Dial Transplant 25:2991–2996View ArticlePubMedGoogle Scholar
- Operating Report (2008) National Health Insurance Administration, Ministry of Health and Welfare, Taiwan. http://www.nhi.gov.tw/webdata/webdata.aspx?menu=17&menu_id=1023&WD_ID=1043&webdata_id=3050. Accessed 31 July 2009
- Price CP, Newall RG, Boyd JC (2005) Use of protein:creatinine ratio measurements on random urine samples for prediction of significant proteinuria: a systematic review. Clin Chem 51:1577–1586View ArticlePubMedGoogle Scholar
- Pugia MJ, Wallace JF, Lott JA, Sommer R, Luke KE, Shihabi ZK, Sheehan M, Bucksa JM (2001) Albuminuria and proteinuria in hospitalized patients as measured by quantitative and quantitative and dispstick methods. J Clin Lab Anal 15:295–300View ArticlePubMedGoogle Scholar
- Stevens PE, Levin A (2013) Kidney disease: improving global outcomes chronic kidney disease guideline development work group members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med 158:825–830View ArticlePubMedGoogle Scholar
- Wallace JF, Pugia MJ, Lott JA, Luke KE, Shihabi ZK, Sheehan M, Bucksa JM (2001) Mutisite evaluation of a new dipstick for albumin, protein, and creatinine. J Clin Lab Anal 15:231–235View ArticlePubMedGoogle Scholar
- Wang JM, Lin CY, Tsai FA, Chen JY, Koa YC (2009) Test dipstick for determination of urinary protein, creatinine and protein/creatinine ratio. J Biomed Lab Sci 21:23–28Google Scholar
- Watanabe M, Funabiki K, Tsuge T, Maeda K, Horikoshi S, Tomino Y (2005) Using protein/creatinine ratios in random urine. J Lab Clin Anal 19:160–166View ArticleGoogle Scholar
- Wen CP, Cheng TY, Tsai MK, Chang YC, Chan HT, Tsai SP, Chiang PH, Hsu CC, Sung PK, Hsu YH, Wen SF (2008) All-cause mortality attributable to chronic kidney disease: a prospective cohort study based on 462 293 adults in Taiwan. Lancet 371:2173–2182View ArticlePubMedGoogle Scholar
- Xin G, Wang M, Jiao LL, Xu GB, Wang HY (2004) Protein-to-creatinine ratio in spot urine samples as a predictor of quantitation of proteinuria. Clin Chim Acta 350:35–39View ArticlePubMedGoogle Scholar
- Yamagata K, Iseki K, Nitta K, Imai H, Iino Y, Matsuo S, Makino H, Hishida A (2008) Chronic kidney disease perspectives in Japan and the importance of urinalysis screening. Clin Exp Nephrol 12:1–8View ArticlePubMedGoogle Scholar