Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: https://www.tandfonline.com/loi/ipgm20

Dipstick analysis of urine chemistry: benefits and

limitations of dry chemistry-based assays

Varun Kavuru, Tommy Vu, Lampros Karageorge, Devasmita Choudhury,

Ryan Senger & John Robertson

To cite this article: Varun Kavuru, Tommy Vu, Lampros Karageorge, Devasmita Choudhury, Ryan
Senger & John Robertson (2019): Dipstick analysis of urine chemistry: benefits and limitations of
dry chemistry-based assays, Postgraduate Medicine, DOI: 10.1080/00325481.2019.1679540

To link to this article: https://doi.org/10.1080/00325481.2019.1679540

Accepted author version posted online: 14

Oct 2019.

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 Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group

Journal: Postgraduate Medicine

DOI: 10.1080/00325481.2019.1679540
Dipstick analysis of urine chemistry: benefits and limitations of dry chemistry-based assays

Varun Kavuru1, Tommy Vu2, Lampros Karageorge3, Devasmita Choudhury3, Ryan Senger2,

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John Robertson 3, 4 *
1
Virginia Tech Carilion School of Medicine, Roanoke, VA 24014

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2
Biological Systems Engineering, College of Engineering, Virginia Tech, Blacksburg, VA

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24061
3
Salem Veterans Affairs Medical Center, Salem, VA 24153
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4
Biomedical Engineering and Mechanics, College of Engineering, Virginia Tech, Blacksburg,

VA 24061
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* Corresponding Author

Abstract
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Urinalysis is a commonly utilized laboratory test and analysis of urine has been studied and used

since ancient times. Urine contains a wide array of metabolites that can provide information
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regarding the current physiologic state of the body and clinical manifestations of disease. In this
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review, we discuss the mechanics of the dry chemistry component of the urine dipstick such as

the reaction principles underlying various assays and potential effects of collection and storage
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on results. Additionally, we discuss the benefits and limitations of the urine dipstick as it pertains

to its use as a low cost tool in point-of-care settings and the reasoning for a lack of its use as a

broad screening tool.

Keywords: urinalysis, dipstick, dry chemistry, urine, assay principles

Disclosures: No potential conflict of interest reported by the authors.

Information Classification: General

 Corresponding Author: Dr. John L. Robertson, 147 Kelly Hall, Virginia Tech, 325 Stanger St.,

Blacksburg, VA, 24061 E-mail: drbob@vt.edu Phone: 540-239-0169

Dipstick analysis of urine chemistry: benefits and limitations of dry chemistry-based assays

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Varun Kavuru1, Tommy Vu2, Lampros Karageorge3, Devasmita Choudhury3, Ryan Senger2,

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John Robertson 3, 4

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1
Virginia Tech Carilion School of Medicine, Roanoke, VA 24014
2
Biological Systems Engineering, College of Engineering, Virginia Tech, Blacksburg, VA

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24061 an
3
Salem Veterans Affairs Medical Center, Salem, VA 24153
4
Biomedical Engineering and Mechanics, College of Engineering, Virginia Tech, Blacksburg,
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VA 24061
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Corresponding Author

Corresponding Author: Dr. John L. Robertson, 147 Kelly Hall, Virginia Tech, 325 Stanger St.,
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Blacksburg, VA, 24061 E-mail: drbob@vt.edu

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Information Classification: General

 Abstract

Urinalysis is a commonly utilized laboratory test and analysis of urine has been studied and used

since ancient times. Urine contains a wide array of metabolites that can provide information

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ip
regarding the current physiologic state of the body and clinical manifestations of disease. In this

review, we discuss the mechanics of the dry chemistry component of the urine dipstick such as

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the reaction principles underlying various assays and potential effects of collection and storage

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on results. Additionally, we discuss the benefits and limitations of the urine dipstick as it pertains

to its use as a low cost tool in point-of-care settings and the reasoning for a lack of its use as a
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broad screening tool.

Keywords: urinalysis, dipstick, dry chemistry, urine, assay principles

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Introduction
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Urine is a biologically-active fluid that uniquely reflects a multitude of complex physiologic

activities of the kidneys, specifically, and the body, in general. Details of urine formation in
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health and disease are widely described in many physiology texts [1,2], and hundreds of review
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papers (not referenced here). Evaluation of urine composition is important because urine

formation reflects metabolism in health and disease. In this sense, urine can act as a monitor of
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some aspects of the urinary tract.

The analysis of urine physical properties, chemical constituents, and suspended particulates

(cells, crystals, biological debris) has been an important medical diagnostic procedure for

thousands of years [3, 4]. Simple, inexpensive testing (visual observation of color and turbidity,

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 odor detection, refractometry for determination of specific gravity, dipstick analysis of

common/diagnostically important chemical constituents) can and is often done by physicians and

trained healthcare professionals in point-of-care (POC) settings (offices, hospitals). Microscopic

analysis of suspended particulates (“urine sediment”) is best done by those trained in urine

sediment analysis and typically occurs in the clinical laboratories. The evaluation of urine

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sediments is not discussed in this review.

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Results of visual characterization and dipstick testing (in samples that have been properly

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collected [see below]) can be very helpful in triggering more rigorous patient evaluation. For

example, gross turbidity invariably indicates a need for sample centrifugation and sediment
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evaluation. Intense, yellow-orange color and high urine specific gravity may be indicative of

dehydration, the presence of chromogenic drug metabolites (rifampin [Rifadin®],

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phenazopyridine [Pyridium®], sulfasalazine [Azulfidine®], isoniazid [Nydrazid®]), vitamin and

dietary plant metabolites, and a number of other normal and abnormal states of health and
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disease.
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Therefore, an understanding of the value and limitations of dipstick evaluations of urine

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chemistry becomes important for timely patient care, in initiating further sensitive diagnostic

evaluation, and assessing the value of such tests for ‘routine screening’ to detect incipient
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disease. The mechanics, value, and limitations of urine dipstick testing are the subjects of this

review.

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1. Urine sample collection, handling, storage

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 The quality of information derived from urinalysis is highly dependent on proper collection,

handling, and storage prior to analysis [5,6,7]. Urine is sterile when formed by healthy kidneys.

However contamination of urine occurs by microorganisms that inhabit the urinary tract and

external genitalia. Methods of urine collection include midstream clean-catch void,

catheterization of the bladder, and cystocentesis (suprapubic aspiration). Each method varies in

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degree of invasiveness and ease of collection. Midstream clean-catch void is the most common

method of urine collection [8]. While intended to minimize contamination without being

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invasive, some data suggests that midstream clean-catch samples do not necessarily decrease

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contamination rates when compared with free catch (no cleaning, no midstream) in patients with

evidence of urinary tract disease [9]. A substantive body of literature however, suggests that
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improvements in contamination rates are associated with specific portions of the midstream

clean-catch procedure such as spreading the labia or cleaning the perineum, and that this
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improvement may be more pronounced in male patients performing midstream catch as opposed

to free catch [7]. Additionally, this apparent lack of improvement in contamination rates across
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some groups may be due to a lack of proper education and explanation to patients as to properly

perform the midstream clean-catch technique [10].

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For purposes of chemical (dipstick) analysis, if uncontaminated urine samples are analyzed

within 1-4 hours, preservatives are usually not necessary. Virtually all clean -catch urine
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specimens that are not preserved either chemically or with a range of cold temperatures will have

contaminant bacterial growth within 12-24 hours, rendering them unsuitable for dipstick or other

urinalysis [11,12]; however, the addition of some preservatives may affect chemical assays

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 (elaborated below) [13]. In more rare cases where urine cannot be analyzed immediately or for

the purposes of clinical research, it may be necessary to store samples for longer than 24 hours.

Urine specimens kept at room temperature for greater than 4 hours show significant growth of

contaminating microorganisms [7]. Storing urine at cooler temperatures such as 4°C, -20°C, or -

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80°C can prevent degradation of the samples. Ideal temperature may vary depending upon the

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desired measurement. For example, osmolality of urine samples has been shown to be stable at

room temperature and 4°C for 4 and 5 days respectively but for >14 days at -20°C [14]. Even

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cooler temperatures as low as -40°C and -80°C have been shown to be effective for preserving

albumin-to-creatinine ratios in urines samples for as long as up to 6 months both with and
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without preservatives added [15]. Varying storage temperatures of urine samples affects urine
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metabolomic profiles which can be seen with results on mass spectroscopy. Investigators note

variable decreases in the concentrations of branched chained amino acids (valine, leucine, for
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example)) and other metabolites (hexose H1, for example) attributable to the activity of enzyme

complexes over a variety of temperature settings (-80°C, -40°C, 4°C, 20°C) and multiple time
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points (0, 2, 8, 24 hours). This group recommended that urine be transported at temperatures at

least as low as -20°C to ensure integrity of samples and to prevent excessive cycles of freezing
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and thawing, which was also shown to affect the metabolomic profile [16].
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Specimens not appropriately preserved can have particles lyse due to low osmolality, low

specific gravity, and higher pH. A variety of preservatives are used depending upon need. Boric

acid affects various reactions on a test strip and can also inhibit the growth of some bacteria. In

some cases, bacterial overgrowth may be undesirable and thus sodium azide may be used as for

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 prevention of this. Formaldehyde use lowers specimen pH and provides false positive results for

leukocyte esterase, peroxidase reaction, and the presence of urobilinogen. Mercury salts, on the

other hand, lead to false negative results for leukocyte esterase [5]. Chlorhexidine solutions can

be advantageous when urine is transported between healthcare services, but samples are best kept

at room temperature as decreased WBC counts and calcium oxalate can be found in samples kept

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on ice [17]. In summary, each preservative has specific situational uses but also comes with

particular disadvantages.

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2. Overview of dipstick analysis of urine chemical composition and assay principles

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In practice, dipstick/dry chemistry analysis involves spotting urine onto different portions of a

dipstick, allowing a timed reaction to take place, and then comparing an associated color change
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on the dipstick to a reference standard to determine a positive or negative result. The color

change is typically triggered by reaction of a chromogenic compound with another reaction

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product produced by interaction of the sample and dipstick reagent. For example, heme (from

hemoglobin) and glucose are detected by reaction of these compounds with peroxidases
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incorporated in the dipstick and subsequent generation of a chromogen end-product that can be
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evaluated [18]. Other common chemical reactions include binding of the dye compounds,

enzymatic, immunologic, and catalysis of oxidation-reduction reactions [19] (Table 1).

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Virtually all dipstick/dry chemistry analyses rely largely on colorimetry, with the intensity of
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color change proportional to the concentration of the analyte being measured. The color is then

matched against a color reference chart to subjectively measure analyte concentration. These

manual/visual evaluations may be imprecise, depending on the visual acuity and color vision

fidelity of the observer.

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 Over the past 20 years, a variety of electronic technologies have significantly improved the

interpretation of color reaction products on dipsticks. Portable (handheld) dipstick readers have

become ubiquitous in primary care and hospital settings, as well as in the consumer market.

They are convenient, economical, and provide rapid, accurate results, depending on specimen

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handling, preservation, and quality. Such devices, based on electronics that convert photonic

energy [from colored reaction products) to electronic signals (CMOS – complementary metal

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oxide semiconductor devices), have reached a level of accuracy and precision that allows

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generation of semi-quantitative/quantitative data. This type of technology is also present in

benchtop and larger laboratory automated systems that use dipstick/dry chemistry, such as the
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Beckman Coulter IRICELL™,(Beckman Coulter Inc., Atlanta, GA), for example. . Automated

technologies increase specimen throughput, minimize specimen handling, reduce manual labor,
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and speed delivery of results to patient records and clinical databases, but still employ the

fundamental dry chemistry technologies that evolved decades ago. These electronic
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technologies, and their use in dipstick interpretation, have been the subject of several excellent

papers and reviews; the interested reader is directed to them [20-25]. Recently, ‘lab on a chip’
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dipstick readers, that can be used with smartphone technology, have been described in the
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literature [26].
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Dipstick/dry chemistry analysis can also provide useful information about other physical and

chemical properties of the urine sample. For osmolarity, a complexing agent in the dipstick will

release protons when in the presence of cations, which reacts with the dye indicator compound

bromthymol blue, producing a color change [18]. Sample pH can be determined within a range

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 of 5.0-8.5, although deviations can occur toward the ends of this range (<5.5 and >7.5). The

preferred and most accurate method to measure pH at those levels is use of a glass electrode [18].

Hemoglobin

Dipsticks can detect hemoglobin due to the heme moiety, which has pseudo-peroxidase activity

that catalyzes the reaction of peroxide and a chromogen molecule to produce a colored reaction

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product. The oxidation of a benzidine compound via reduction of a buffered organic peroxide

provides a positive result [27]. This test thus can detect hematuria, hemoglobinuria, or

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myoglobinuria, as all involve the heme moiety reaction [28].

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Pseudo-peroxidases are hemoproteins that have active sites that can catalyze the H2O2 reduction
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to water. Molecules that meet specific criteria can be considered to have peroxidase-like activity

and could theoretically trigger a false positive result. These criteria include: molecules that have
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iron in the ferric form (Fe (III)), five coordination bonds and an H2O molecule on the distal side

of the heme molecule that is replaced with H2O2, and specific arrangements of amino acids
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(conserved histidine-arginine couple) [29]. There does not seem to be extensive documented
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evidence in the literature of porphyrin molecules or patients with porphyrias triggering ‘positive’

results for hematuria, however if a molecule in the pathway of hemoglobin synthesis were to
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meet the pseudoperoxidase criteria, then it could theoretically trigger a positive result.
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False positive results for hematuria may be produced in instances of hemoglobinuria,

myoglobinuria, and from exogenous pseudo-peroxidases produced by contaminating bacteria

such as Lactobacillus species [27]. Strong reducing agents such as ascorbic acid can also cause

false-negative results [18]. In combination with a microscopic urinalysis for RBC count a

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 dipstick result for ‘blood’ (hematuria) can provide insight and guidance to whether a patient’s

macroscopically discolored urine may be the result of hematuria, hemoglobinuria,

myoglobinuria, pseudo-hematuria (drugs, dyes, etc.) [30].

Glucose

For glucose detection, it is the interaction of glucose with glucose oxidase that forms D-glucono-

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1,5-lactone and hydrogen peroxide. A peroxidase then catalyzes the reaction of hydrogen

peroxide with a reduced chromogen. Ascorbic acid (a reducing agent) and some bacteria may

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cause a false negative result, while oxidizing agents and hydrochloric acid can cause false

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positive results [18].

Proteinuria
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Dipsticks are commonly used to test for proteinuria. They can give a general estimate of the

amount of protein present in a sample. This is because the concentration of protein in a buffer
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will cause a proportional change in pH. The dipstick method is most sensitive to albumin and

less sensitive to other proteins. The color of the dipstick can change from pale green, to green, to
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blue and offers an approximate quantification that is noted as 0 to plus-3 (+++) or plus-4 (++++)

depending upon the color [18].

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In the absence of protein, the dipstick will remain yellow. Protein will disrupt the dye and buffer

on the dipstick and cause a green color to develop. Causes for a false positive result can include:
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alkaline urine (pH > 7.5), overly length time of urine immersion, highly concentrated urine (less

hydrated states), gross hematuria, pus, semen, vaginal secretions, or some drugs such as

penicillin. False negative results can occur if the urine is extremely dilute such that the protein is

Information Classification: General

 not adequately detected by the dipstick, or if the protein is significantly lower in molecular

weight (light chains) and other non-albumin proteins [31].

While glomerular disease is more common, tubular pathology can also result in proteinuria. This

occurs when proteins, of lower molecular weight, are unable to be reabsorbed from the filtrate

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due to a tubulointerstitial pathological process. This proteinuria is generally less than 2 grams in

24 hours and may result in a false negative dipstick result [31].

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Protein light chains such as Bence-Jones proteins (kappa and lambda light chains) are not

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detected by dipstick and require additional testing. If there is suspicion for these smaller protein

chains, a sulfosalicylic acid test may be performed, however the definitive test for monoclonal
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light chains would be electrophoresis [32,33].

Leukocytes – Esterase Activity

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Dipsticks can provide insight into the presence of leukocytes in urine by means of indoxyl

esterase activity. This enzyme is released in the lysis of neutrophils and macrophages. Samples
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that have an alkaline pH or low densities due to the favored lysis of leukocytes in those
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environments will result in false positives, while conversely, high-density samples will decrease

sensitivity to leukocytes. High levels of glucose and protein, as well as some drugs (e.g.
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tetracyclines) can provide false negative results for leukocytes. Leukocytes will lyse and release

indoxyl esterase, which will catalyze reactions involving indoxyl or pyrrole carbonic acid esters,
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and result in a product that interacts with a diazonium salt to produce color [34].

Nitrites

Dipstick tests for nitrites can be used as a proxy test for some Gram-negative bacteria that utilize

the nitrate reductase to reduce nitrates into nitrites. In order for this test to detect nitrites, there

Information Classification: General

 first must be sufficient nitrates, typically from a vegetable-rich diet. The nitrites first react with

p-arsanilic acid on the dipstick to create a diazonium compound which then couples with a

quinolone compound on the dipstick to produce a pink color [34].

Ketones

The dipstick test to detect ketones such acetoacetate and acetone, involves their reaction with

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nitroprusside or nitroferricyanide and glycine [28]. Most test strips will detect acetoacetate,

which is the first ketone body created from acetyl-CoA, and some brands will detect acetone,

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however none detect beta-hydroxybutyric acid [34]. Ketostix® reagent strips (Siemens

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Healthcare Diagnostics Inc./Bayer Diagnostics, Tarrytown, NY) were first demonstrated to be

more effective than test tube methods of ketone detection in 1958 [35]. Most modern test strips
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will detect acetoacetate, which is the first ketone body created from acetyl-CoA, and some

brands will detect acetone, however none detect beta-hydroxybutyric acid [34]. Beta-
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hydroxybutyric acid is the predominant ketone body present and is best tested with its own assay

using capillary blood [36]. Due to the predominance of beta-hydroxybutyric acid, the
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nitroprusside test may be weakly positive in some cases of increased ketones such as alcoholic

ketoacidosis [37]. In diabetic ketosis and ketoacidosis, capillary blood ketone testing was found
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to have fewer false positive and negative results than dipstick urine ketone testing [38].
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Bilirubin and Urobilinogen

Only bilirubin that is conjugated with glucuronic acid can pass through the glomerulus. Bilirubin
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is also converted by bacterial enzymes into urobilinogen in the intestines, which can then be

oxidized into urobilin, which has a brown-pigmented color. These compounds can be present in

the urine. Bilirubin is normally not present in urine in any significant quantity, however

urobilinogen can be present normally. [34].

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 Many dipsticks that screen for bilirubin make use of a coupling reaction that occurs in the

presence of acid between bilirubin and a diazonium salt, however the specific salt used and

resulting color can vary between manufacturers. These sticks are ready after 30-60 seconds and

the typical resulting colors range from shades of tan to purple. Common diazonium salt

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indicators used by different dipsticks include: 2,6-dichlorobenzene-diazoniuim-tetrafluoroborate

in the Chemistrip® (Hoffmann-LaRoche Ltd., Basel, Switzerland)) and 2,4-dichloroanaline

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diazonium salt (Siemens Healthcare Diagnostics, Tarrytown, NY) [34].

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For urobilinogen dipstick screening, the Ehrlich aldehyde reaction is utilized. In this reaction, an

aldehyde (p-dimethylaminobenzaldehyde) or diazonium salt compound is used in an acid

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condition to react with urobilinogen to produce a red or pink colored azo dye product. The

dipstick is read after 30-60 seconds [34]. Urobilinogen may be elevated in situations of increased
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hemolysis and hepatocellular disease. It may also be decreased with antibiotic use due to a

change in the microbiota [28]. Since a positive result on this test may be normal, the screening of
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bilirubin is more useful for the early detection of pathology than urobilinogen.
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3. Benefits - why are dipsticks used?

Urine dipsticks are widely used for a number of reasons. As depicted above in the section on
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assay principles, dipsticks can be used to test for a variety of factors that can help with clinical

decision-making and trigger further testing or investigation. Urine dipsticks are well poised to be

used in point-of-care settings due to their ease of use. This type of testing, as opposed to

traditional central laboratory testing has some advantages.

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 Point-of-care testing (POCT) can improve efficiency and metrics in primary care clinics by

allowing for faster communication with patients prior to them leaving the clinic, as well as

saving costs on more expensive tests that may not be necessary [39]. While initially more

expensive than central laboratory testing, POCT can reduce costs over time by reducing turn

around time, and reducing patient time spent in the emergency department (ED) or hospital

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depending upon the situation [40]. Use of a point-of-care comprehensive metabolic panel has

been shown to reduce ED length of stay in patients either admitted to the hospital or discharged

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to home as compared to central laboratory testing [41].

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POCT urine analyzers can be used to read the results of dipstick dry chemistry, which can appear
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very shortly after exposure to urine, with accuracy comparable to or exceeding visual analysis

[42]. This automation can further improve the efficiency of point-of-care urinalysis. Automated
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dipstick tools have been shown to be sensitive for diagnosing urinary tract infection (UTI) and

can provide further justification to move forward with urine culture, although flow cytometry
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may provide even better predictions [43]. As stated in the section on assay principles, a standard

urine dipstick can be used to assess for a variety of enzymes and the presence of particles.
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Further, regardless of automation, dipsticks themselves are relatively straightforward to use in

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the clinic and can be utilized in settings with fewer resources and technology [18]. Automated

dipstick analysis has been combined with flow cytometry to construct devices that can cross-
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check for discrepancies between tests, thus reducing the turnaround time necessary to check

samples manually in which results may be incorrect [44]. As noted previously, there is robust

literature describing the benefits accrued from both handheld and automated systems that use

electronic technologies to interpret chemical reactions on dipsticks.

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 Economically, urine dipsticks are among some of the most affordable and least expensive

laboratory tests available. The cost to a primary care clinic of running a test including specimen

collection, processing, labor costs, personal protective equipment (gloves), and the physical

dipstick itself can be estimated to total $3.05 [45]. The retail price of a packet of 100 Chemstrip

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9® dipsticks costs $57.45 at the time of this writing, amounting to less than $0.60 per stick [46].

The estimated cost of the automated urinalysis test at the Veterans Affairs Medical Center in

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Salem, VA, including cost of labor for technicians, phlebotomy and bundled cost of a

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microscopic analysis, is less than $5.00. Average combined time for collection and analysis is

approximately 6 minutes (April 2019 email from S.T. Stoneman, Laboratory Information
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Manager, MT to Varun Kavuru [VA urine dipstick cost]; unreferenced).
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Dipsticks themselves are fairly inexpensive tests, but a positive result for proteinuria will result

in further confirmatory, quantitative testing such as a 24-hour urine collection or albumin-to-

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creatinine ratio (ACR ratio) [31]. The National Kidney Foundation also supports the use of ACR

ratio or albumin-specific dipsticks after a positive dipstick for proteinuria in its information for
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patients [47]. In addition to the above quantitative tests, a positive proteinuria dipstick result can
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trigger further microscopic analysis of urine sediment which may provide further findings of

casts that can provide further insight into a pathologic process [31]. In the cases of false
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positives, this will result in more cost as tests are ordered with no true need to calculate protein

loss, however a negative screening dipstick result would not trigger the further more expensive

testing and provides a quick less expensive POC option for testing.

5. Limitations – why shouldn’t dipsticks be used

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 As noted, dipstick/dry chemistry tests can be useful POC screening tests to trigger more

definitive diagnostic evaluation, but are not useful for providing a definitive diagnosis alone.

While a single, dipstick/dry chemistry measurement of a suitable urine specimen at a single time

point may provide temporally useful information, the results are not intended to be diagnostic.

Dipstick/dry chemistry testing is not generally accepted as a means to screen large populations

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for the presence/absence of disease (see below).

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The limitations of such dipstick/dry chemistry tests (whether at a POC or in an automated

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laboratory setting) are well-known and include:

• They may be inaccurate in quantifying important indicators of disease including glucose,

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protein, albumin, hemoglobin (see examples and discussion, below), although recent

advances in the analysis of dipstick reactions (colors) with electronic technology can
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produce semi-quantitative/quantitative data for further interpretation,

• Their use in determining the presence/absence of common conditions such as urinary

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tract infections may be problematic and is considered debatable, (especially in urgent

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POC settings) [48,10,49-54],

• They are not diagnostic for any particular disease and may only provide a simple,
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suggestive result for a variety of simple or more complex pathologies,

• Interfering compounds, including therapeutic drugs, vitamins/supplements, chemical

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preservatives and detergents (used during sample collection) may invalidate test results,

• Values obtained by dipstick/dry chemistry measurement need to be interpreted in the

context of urine concentration, measured as urine specific gravity, and time of sample

collection [55],

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 • Values obtained by dipstick/dry chemistry measurements need to be interpreted in the

context of urine pH, since dipstick chemical reactions may be suboptimal at the extremes

of urine pH,

• Re-testing of individual samples (i.e., repeated dipstick tests on the same sample) is

rarely done,

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• Proximately timed, serial samples from the same individual are rarely tested,

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• False positive test results clearly may mislead and channel diagnostic thinking among

healthcare providers, and may create needless anxiety for patients,

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• False negative results may discourage further diagnostic evaluation,

• POC interpretation (visual inspection) is subjective, based on color vision acuity of the
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observer, lighting conditions, and correct timing of test interpretation (at the chemical
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reaction maximum), and,

• The use of dipstick/dry chemistry test strips that are nearing expiration or which have
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been improperly stored is problematic due to the possibility of false positives.

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Two examples illustrate some of these limitations.

Both macroscopic and microscopic hematuria can be detected with dipstick/dry chemistry
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testing. There is a multitude of common and uncommon causes of hematuria, including urinary

tract infection, normal menstruation, abnormal menstruation, urinary tract calculi,

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glomerulonephritis, pyelonephritis, and genitourinary tract neoplasms, to name a few. Clearly,

the dipstick test was not designed to and cannot differentiate among these and many other

causes.

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 Dipstick testing is rarely needed or used when macroscopic hematuria is seen. When

accompanied by pain, urinary tract infection or the presence of calculi are common, suspected

etiologies. When pain is not present, there is suspicion of primary glomerular disease or the

presence of urinary tract neoplasia. Further diagnostics may follow such as urine microscopy

and cytology followed by referral to a urologist if no clear etiology is determined. This may lead

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to further more testing such as CT intravenous pyelogram and cystoscopy [56]. In the setting of

macroscopic hematuria in the ED, use of dipsticks may still provide utility in evaluating the

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presence of infection as a possibly cause and can be consider part of the workup [57].

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However, the detection of asymptomatic microscopic hematuria in routine urinalysis specimens
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is common (seen in up to 18% of specimens) with dipstick testing [58,59]. Given a positive test

result, the patient and physician must then decide how to proceed, including 1) whether or not to
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repeat the urinalysis, including urinary cytology, and/or 2) pursue diagnostic imaging, and/or 3)

consider cystoscopy for occult lesions (such as bladder cancer). The diagnostic path to be
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followed has been the subject of considerable debate [60,61]. In a recent study, Matulewicz and

co-workers considered the use of dipsticks to detect microhematuria a useful diagnostic

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procedure for detection of bladder cancer [62], however, there is no widely accepted algorithm
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that is followed when “dipstick hematuria” is found in routine screening urinalyses [63-65].

The presence of protein in urine is a significant indicator for further diagnostic evaluation, if
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incidental specimen contamination is ruled out (i.e, from secretions and cells in free-catch

specimens). While protein in urine may indicate renal disease, it is difficult to discern early

stages of disease (i.e., before albumin appears in urine), and free-catch specimens may be

Information Classification: General

 contaminated with proteins and secretions from other tissues in the urinary and genital tracts

[66].

In the past, regular measurement of urine glucose (for the purposes of adjusting insulin dosage)

allowed incidental measurement of urine protein. With the widespread acceptance of blood

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glucose monitoring for management of diabetes, routine collection of urine from diabetics has

decreased. It is, however, well-established that the development of microalbuminuria (defined

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here as the presense of small amounts of albumin in urine) is a harbinger of renal dysfunction in

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diabetes mellitus, and that regular screening of the urine of diabetics for the presence of albumin

is both necessary and standard-of-care [67,68].

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It is apparent that an economical, home-based test (i.e., dipstick/dry chemistry assay) could be
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useful in early detection of diabetes-associated renal dysfunction. In a home-testing based

study of a cohort of patients with type 2 diabetes, Nagrebetsky and coworkers found that
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dipstick-based testing did not reliably detect microalbuminuria, compared to laboratory-based

testing of urine albumin-creatinine ratio [69]. Using systematic literature review and data meta-
pt

analysis, Wu and coworkers found that laboratory-based testing of urinary albumin concentration
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and albumin-creatinine ratio, although more expensive and less convenient than dipsticks, were

more reliably sensitive and specific tests for diabetes-associated microalbuminuria [70].
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Zeller et al. conducted a study in which they assessed the diagnostic accuracy of transferrinuria

and an albumin-specific dipstick for detecting microalbuminuria in hypertensive non-diabetic

patients. These albumin-specific dipsticks such as Micral® (Hoffmann-LaRoche Ltd., Basel,

Information Classification: General

 Switzerland) strips were found to be less sensitive and specific than transferrin-to-creatinine

ratios. The authors noted that prior studies of this type of dipstick had largely been done in

diabetic patients. They found the test to have more false positives than false negatives, but

deemed this acceptable for the screening purposes of the test. They found the negative predictive

value of the albumin-specific dipsticks to be high (92%) and concluded that the test provides a

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simple, useful, and cost-effective method of screening for microalbuminuria in hypertensive

patients in a primary care setting [71].

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The presence of albumin (and other proteins) in urine is an accepted indicator of the presence

and severity of chronic kidney disease (CKD) and regular monitoring of the urine of patients in
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early stages of CKD may be quite useful in detecting responses to medical/lifestyle management,

as well as detecting progression of disease. Although economical and convenient (see above),
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dipstick/dry chemistry testing for the presence of protein is unlikely to be either sufficiently

sensitive or specific in management of CKD. Abnormalities in the composition of urine

ed

sediments (hematuria, pyuria, casts, and other changes) also are considered potential indicators

of CKD and may be of greater value than single spot measurements of urine proteins with
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dipstick assays. Other molecular indicators of CKD, including the presence of complex
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metabolic by-products collectively termed “uremic solutes,” are not measured routinely in serum

or urine, either by dipstick/dry chemistry assays or standard laboratory automated urinalysis, but
Ac

may become important diagnostic biomarkers, since they are important in the pathogenesis/

progression of CKD and systemic co-morbidities such as cardiovascular disease [72].

Information Classification: General

 A 2014 systemic review of guidelines for the use of urinary dipsticks for screening across 67

organizations in 9 countries found a lack of agreement in guidance amongst organizations for the

use of dipsticks for screening for some assays. Regarding screening for hemoglobin with

dipsticks, UK organizations of nephrology, urology, and the UK National screening committee

recommended against screening while some organizations made no comment or

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recommendation. Regarding screenings for leukocyte esterase and nitrites, all organizations

recommended against screening asymptomatic non-pregnant patients. Additionally, regarding

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screening for proteinuria, the UK National Screening Committee and Canadian Society of

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Nephrology recommended against screening with dipsticks. The National Kidney Foundation

K/DOQI guideline recommends screening patients at high risk for CKD but recommended the
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use of albumin-creatinine ratios or albumin-specific dipsticks. Overall this study found a lack of

clear consensus amongst guidelines across multiple organizations and countries for the use of
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dipsticks for screening purposes [73].

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Conclusion

In summary, urine dipstick dry chemistry is easy to use, inexpensive, and has the ability to assess
pt

a variety of assay principles in a short period of time, making it ideal for a POCT setting. It is
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critical that careful attention is paid to the storage conditions of urine samples that are stored for

longer than two hours. The use of preservatives and cold temperature ranging from -80C to 4C
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can extend the shelf life of urine and prevent the overgrowth of microorganisms, breakdown of

metabolites, and subsequent test results on a dry chemistry dipstick. However, one must note that

no one preservative substance is capable of perfectly preserving urine samples and without affect

on sample composition.

Information Classification: General

 Urine dry chemistry is capable of assessing a wide array of assays such as pH, osmolality,

hemoglobin/myoglobin/hematuria, leukocyte esterase, glucose, proteinuria, nitrites, ketones, and

bilirubin. These findings can then provide a basis for further testing based upon clinical

suspicion. Examples include UTIs, diabetes mellitus (as well as diabetic ketoacidosis),

glomerular damage, metabolic defects, and even hepatic dysfunction.

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Other benefits of dipsticks include their ability to be automated to reduce human error and labor

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as well as their ability to be utilized in a point-of-care setting. The simple and fast nature of the

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test, dripping urine onto the test strip, or dipping the test strip into a urine sample and allowing

the relevant reaction to occur lends itself able to be done very close to the patient’s bedside.
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These factors allow for the potential for the test result to be returned to the patient very early and

may prevent the need for a second visit. In an emergent care setting, it can allow for faster
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discharge or admission and facilitate decision making between provider and patient.
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Despite its advantages, dipstick dry chemistry presents a number of limitations to its use as a

broad screening tool. Dipstick dry chemistry alone is often not sufficient for decisions regarding
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clinical management and often prompt or discourage further testing, depending upon dry
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chemistry results. Limitations include a lack of quantifiable results, subject to false positives and

negatives due to various confounding factors in the patients diet or contamination of sample, and
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dipstick interpretation variability. Another example of the limitation of dipsticks is the lack of a

widely accepted diagnostic algorithm for asymptomatic hematuria. Furthermore dipsticks have

not been shown to exhibit sufficient sensitivity for albumin in a routine home testing setting and

other markers such as albumin-to-creatinine ratio have been shown to be more effective for the

Information Classification: General

 detection of diabetes associated microalbuminuria. In conclusion, despite the benefits of their

ease of use, low economic cost, and wide assay, urine dipsticks face a number of limitations in

their use as broad screening tools.

Disclosures:

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The contents of the paper and the opinions expressed within are those of the authors, and it was the
decision of the authors to submit the manuscript for publication.

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No potential conflict of interest reported by the authors.

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Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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 Table 1

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Informattion Classifica
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