Urine That Has Been Supplied for a Drug Test Can Be Frozen and Tested Again at a Later Date.
Biochem Med (Zagreb). 2022 Feb; 24(1): 89–104.
Preanalytical requirements of urinalysis
Joris Delanghe
1Department of Clinical Chemistry, Ghent Academy Hospital, Gent, Belgium
Marijn Speeckaert
2Department of Nephrology, Ghent University Infirmary, Gent, Belgium
Received 2013 Sep 30; Accustomed 2013 November 20.
Abstract
Urine may be a waste matter product, but it contains an enormous amount of information. Well-standardized procedures for drove, send, sample preparation and analysis should become the basis of an effective diagnostic strategy for urinalysis. As reproducibility of urinalysis has been greatly improved due to recent technological progress, preanalytical requirements of urinalysis have gained importance and have go stricter. Since the patients themselves often sample urine specimens, urinalysis is very susceptible to preanalytical bug. Various sampling methods and inappropriate specimen transport can crusade important preanalytical errors. The use of preservatives may be helpful for item analytes. Unfortunately, a universal preservative that allows a complete urinalysis does non (nonetheless) be. The preanalytical aspects are also of major importance for newer applications (eastward.g. metabolomics). The present review deals with the current preanalytical problems and requirements for the most mutual urinary analytes.
Keywords: menses cytometry, preservatives, sample training, urinalysis
Introduction
Urinalysis is the third major diagnostic screening test in the clinical laboratory, but preceded past serum/plasma chemistry profiles and complete claret count analysis (1,2). For decades, microscopic urine sediment analysis has been the gold standard (iii). The introduction of new technologies and automation has improved the accuracy and productivity of the process (4). On the other manus, consolidation of laboratories has increased the physical distance betwixt patient and laboratory, which creates a major preanalytical claiming. It is mandatory to focus on the preanalytical phase in order to improve the reliability of examination results (v) and to lower the costs of health care (six). In the clinical laboratory, total quality could be defined every bit the guarantee of a correctly performed activeness throughout the total testing process, providing valuable medical diagnosis and efficient patient care. Improvements in both reliability and standardization of belittling techniques, reagents and instrumentation have contributed to a remarkable 10-fold reduction in the analytical fault rate over the last 30 years. Furthermore, also progress in information technology and quality assurance methods take contributed to a farther reduction of diagnostic errors. Nevertheless, the lion share of errors in laboratory diagnostics (and in urinalysis in particular) falls outside the belittling stage; both preanalytical and postanalytical steps are much more vulnerable (7).
Various subphases take been identified in the pre-belittling stage of urinalysis. Need for the test, collection and transport of the sample to the laboratory, receipt of the specimen by the laboratory and sample training and transport to the proper laboratory section for testing (eight) tin can exist important potential sources of error. As more effort needs to be spent in the preanalytical phase for the further reduction of errors (ix), in the nowadays paper we requite an overview of the preanalytical challenges of urinalysis.
Patient preparation and sampling procedures
The laboratory is responsible for right information regarding optimal patient preparation and best sampling procedure. Interpretation of test results is only possible when these conditions are fulfilled. Informing the patient goes far beyond just explaining the practical aspects of urine sampling. More specifically, the outcome of possible biological confounders such equally dietary intake, diuresis, do and other interferents, should exist emphasized. If necessary, illustrated instructions for sampling can exist provided (10). Despite the existing guidelines, the importance of a proper preanalytical procedure for collecting urine specimens is usually non known by the patients. In a recent paper, Miler et al. showed that a 24-60 minutes urine sample was not properly nerveless in more than one-half of the informed outpatients, which were oft older (generally > 65 years) and suffering from a chronic disease. The prescribed instructions were not followed, some volume of the urine sample was discarded or an improper container was used. To subtract the number of errors in the preanalytical phase, laboratory staff, general practitioners and patients should exist educated and an active promoting of the preanalytical procedures by the laboratory staff should exist encouraged. In case of an incorrect sample procedure, the urine collection should be repeated (11).
The quality of the reported results could also be influenced by variables in specimen processing. Sample preparation is more essential for different particle analysis techniques in comparison with urine test strip analysis and microbiological civilisation. Every bit an instance of the importance of interferents, the influence of commercially available baby soaps on tetrahydrocannabinol (THC) immunoassays can exist mentioned. Beyond healthcare, newborn drug screening plays besides an of import role in the legal domain. Mixtures of drug-free urine with various products that commonly contact newborns were tested using immunoassays. Addition of variable commercially available infant soaps to drug-gratuitous urine resulted in a measurable response in THC immunoassays. Due to the presence of surfactants with the THC analysis, soap and wash products used for newborn and infant intendance can potentially cause simulated positive screening test results, leading to interest past social services or false child corruption allegations (12).
Which precautions should be implemented?
Minimizing contamination tin can already exist achieved by implementation of unproblematic precautive measures. A 20% reduction of the number of faux positive urine cultures can exist achieved by washing the glans penis of men or the introitus of women (10,13,14). Due to the influence on the viability of bacteria, the use of soap or antiseptics is not recommended (10,15).
Which sampling procedure to choose for urinalysis?
A large amount of sampling procedures is available with specific advantages and disadvantages. When deciding the best process, one should take into consideration the patient's characteristics (suspected microorganisms or presence of a urinary catheter). Sample quality can only be warranted if standardized instructions for urine collection are bachelor (10,thirteen). Clean-catch urine or midstream portions of starting time morning time urine samples collected in a sterile urine container are the most ordinarily obtained specimens in routine exercise. However, overnight bacterial growth in the float is likely, which tin can affect casts and cells. Morphological studies showed a higher reproducibility when incubation time was ± 1–2 h. Therefore, using 2nd morning urine specimens is sometimes recommended (urine samples voided 2–iv h after the first morning time urine) (16). In a recent multicenter report (17), results obtained from first-voided and mid-stream urine samples were compared. In salubrious subjects, two consecutive samples of the first morning micturition were collected by a vacuum organisation, the commencement from the showtime-void and the 2d from the mid-stream. Routine urinalysis was performed using dip-stick automatic analyzers and automated particle analyzers. Counts of epithelial cells, erythrocytes and leukocytes, only not for casts were significantly college in the first-voided samples. A significantly college count of epithelial cells, erythrocytes and leukocytes was also observed between females and males in first-voided samples, whereas no significant deviation could be found in mid-stream samples. Overall prevalence of subjects with cellular elements count exceeding upper reference limits was also higher in first-voided than in mid-stream samples. Mid-stream urine was confirmed every bit the most appropriate sample, since the presence of contaminating elements, such as leaner, analytes and formed particles are minimized (10).
The European Confederation of Laboratory Medicine (ECLM) has proposed a nomenclature of reference measurement procedures for urine measurements. Unlike levels of accuracy accept been defined (level ane–4). Level 1 represents rapid or screening methods, amenable to point-of-care testing, frequently with an ordinal scale issue. Some may be suitable every bit screening methods for larger laboratories if specificity, sensitivity, or both are high enough. Level two has been defined every bit methods suitable for routine laboratories; many of them will be automated or could exist automated in the hereafter. Level 3 represents the "Country of the fine art" methods whose performance is satisfactory enough for purposes of comparison. Finally, level iv stands for best methods (principal reference measurement procedures = reference and definitive methods). Based on those guidelines, erythrocytes and leukocytes can be examined by strip exam (level ane), standardized urine sediment (level two) or advanced bedroom counting (level three); albumin and other proteins can detected by strip examination (level 1), quantitative field measurement (level two) or accurate measurement traced to the CRM 470 protein standard (level iii); bacterial analysis should be performed by dipslide civilization (level ane), culture with a 1 μL dispensable loop for 24–48 h (level 2) or quantitative titration of 10–100 μL inocula on two different [cysteine lactose electrolyte deficient medium (CLED) and haematin] agar plates (level 3) and urine volume rate (diuresis) could be analysed by strip exam (level i), creatinine and refractometry (level ii) or quantitative measurement of osmolality (level 3) (18).
Which sampling container is preferable?
Collection of urine specimens is a major source of preanalytical variability. A sterile collection is mandatory for bacteriological culture of urine samples. Urine collection container pattern should enable easy sampling, ensuring an optimal ship and allowing sensitive detection of pathogens. Furthermore, they should be costless of interfering agents and made of non-absorbing materials, with no influence on whatsoever analyte. The drove book should be determinant factor for the size of the urine container. Additional requirements may be needed in function of diagnostic procedures (east.g. lite sensitive analytes as porphyrins and urobilinogen require amber-colored urine containers) (8,10). The original primary sample should be divided into different smaller aliquots for morphological, microbiological and chemical analyses to decrease the risk of contamination. Easy filling from master containers without gamble of spillage should be one of the feature of secondary containers. These transparent tubes preferably have a round bottom, which allow a better resuspension of the sediment following centrifugation (10).
For reducing the risk of errors and contamination, commercially bachelor vacuum systems have been adult, allowing direct sample aspiration into a secondary container. Vacuum systems can only be used for chemical analysis and are non recommended for particle analysis. During vacuum aspiration, the pressure level difference results in a desintegration of brittle casts. Vacuum aspiration is responsible for a significant reduction of hyaline and cellular cast counts (respectively at least 58% and 51%) in comparing with conventional exam tubes (four). The reduction of cast counts depends on the vacuum during aspiration (19). A destruction of cellular casts (which are only weakly hold together by the sticky Tamm-Horsfall protein) is observed due to mechanical damage during vacuum aspiration, with a release of their cellular inclusions, every bit demonstrated by an increased corporeality of erythrocytes and leukocytes. Erythrocyte counts in urine specimens were college (> 25% increment) in vacuum tubes than in conventional tubes (4). At this moment, only particle analysis will result in true identification of casts. The available assays measuring Tamm-Horsfall protein can provide data on the presence of casts, without verifying the nature of the casts. The influence of vacuum systems on other elements is limited. No difference in flowcytometric erythrocyte count and the percentage of nonlysed erythrocytes has been observed for urine samples with normal osmolality (conductivity) in conventional and vacuum test tubes. Yet, the erythrocyte count and the pct of nonlysed erythrocytes in vacuum tubes were lower than in conventional urine tubes (minimum 20% and 31% reduction) in samples with depression conductivity. Peroxidase-based haemoglobin dipstick reactions were comparable. Because of the growing importance of (micro)albuminuria in the diagnosis of kidney disease, more attention has been paid to the particular preanalytical aspects of this analyte. At low albumin concentrations, adsorption to the surface of urine containers tin can atomic number 82 to marked relative losses (20). Nonspecific adsorption of urinary albumin was calculated at < 1 mg/Fifty with hydrophilic surfaces and < ii mg/L with nonhydrophilic surfaces. Binding to surfaces may also result in protein denaturation. Addition of nonionic detergents or using hydrophilic surfaces may reduce both adsorption and denaturation. Albumin is relatively stable at the air-liquid interface when rapid mixing generates foaming. Frozen storage at temperatures above −fourscore °C (specially at −20 °C) produces various modifications to the albumin molecule (21).
Transport and preservation
Is it a thing of time?
An increased time lag between sampling and analysis, a lack of temperature control and a lack of addition of a preservative to samples for which urinalysis cannot exist performed within 2 hours of collection, will lower the quality of urinary exam results. Table 1A and 1B give an overview of the stability of different particles and test strip parameters (22). The verbal sampling time and delays exceeding the specified limits should be documented. Point-of-care analyses are not subject to this delay, just may too be afflicted by diverse analytical issues.
Table 1a.
Influence of temperature on stability of particle analysis (adapted from reference 21).
| Particle | −20 °C | 4–eight °C | 20–25 °C |
|---|---|---|---|
| Carmine blood cell | NA | ane–4 h | 1 h - 24 h (> 300 mOsmol/kg) |
| White claret cell | NA | i–4 h | 1 h (pH > 7.5) - 24 h (pH < 6.5) |
| Acanthocytes | NA | ii days | ane mean solar day (> 300 mOsmol/kg) |
| Casts | Non immune | NA | 2 days |
| Leaner | NA | 24 h | ane–2 h |
| Epithelial cells | NA | NA | 3 h |
Table 1b.
Influence of temperature on test strip assay (adapted from reference 21).
| Analyte | 4–eight °C | twenty–25 °C |
|---|---|---|
| Red claret cells | ane–3 h | four–8 h |
| White claret cells | 1 day | 1 solar day |
| Proteins | NA | > ii h (unstable at pH > 7.5) |
| Glucose | 2 h | < 2 h |
| Nitrites | viii h | four days |
Employ of preservatives: why, which and when?
Alkaline pH, low relative density and low osmolality can induce a rapid lysis of some urine particles after collection (22). Improver of stabilizers unremarkably prevents metabolic changes of urine analytes and overgrowth of bacteria. In a recent study, the value of ship tubes containing a preservative for maintenance of the semiquantitative and qualitative cess of urine cultures was again demonstrated, particularly in cases when the sample transport time > 2 h (23). However, preservatives may affect some chemical properties and alter the appearance of particles. An appropriate label conveying a take chances symbol should give information dealing with any preservative (10,xiii,22). Risk of sample dilution and its potential influence on outcome of urine civilization are important issues when using liquid mixtures.
The right preservative to specimen ratio should be respected when samples are preserved for transport and assay (eight). The recommended specimen volume is mostly indicated on the container with a marking line. If too much sample is added to the container, the concentration of the preservative gets too low, reducing the preservative action. In the inverse situation, an excessive amount of preservative may inhibit bacterial growth. The minimal urine volume needed in order to obtain right results has been determined for two unlike preservative-containing systems (24). Traditionally, ethanol (50%) is selected to preserve cellular particles, although simply a partly prevented lysis of reddish and white blood cells is observed. Addition of polyethylene glycol (20 k/L) to the ethanol fixative (Saccomanno's fixative) improves preservation quality (10,25). Lyophilised formulations should be chosen among the commercial preservatives as at that place is no risk of sample dilution of spillage. Also, containers supplemented with boric acid alone or in combination with formic acid or other stabilizing media, are used (10,26). Table 2A depicts the outcome of normally used preservatives on period cytometric particle assay. In contrast to casts, epithelial cells and leukocytes, the stabilization of erythrocytes is extremely difficult, probably due to cellular shrinkage following the add-on of formaldehyde solutions (25).
Table 2a.
Influence of preservatives on particle analysis by menstruum cytometry.
| Particle | Borate + Formiate + Sorbitol | ten mL/50 Formaline 0 .15 mol/L NaCl | fourscore mL/L Ethanol + 20 g/L PEG |
|---|---|---|---|
| Red blood cells | |||
| White blood cells | |||
| Casts | |||
| Epithelial cells | |||
| Leaner |
In office of the required testing, a difference in preservative demands is requested. In detail, laboratories should focus on the analytical test quality, every bit more reliable results ask for stricter pre-analytical demands. Several specific proteins are instable in urine, which could be resolved by inhibition of their degradation by the improver of some preservatives. Although the 24-hour urine collection is the reference method for quantification of stable chemical analytes, contagion, incorrect collection and incorrect calculation of urinary book can cause preanalytic errors. The albumin: creatinine ratio (or protein:creatinine ratio) on a random urine sample, which is non influenced by variation in h2o intake and rate of diuresis, is a recommended alternative (27). Correlation between protein:creatinine ratio and 24-hr poly peptide excretion may non be accurate for proteinuria levels > 1 k/L. For monitoring proteinuria, the reliability of protein:creatinine ratio still needs to be proven (9,22).
When analysis of the examination strip can exist performed within 24 hours and the urine specimen has been refrigerated, no preservatives are needed (ten). Freezing cannot be regarded as an culling for refrigeration in preserving samples for urine examination strip analysis. The selection of the preservative partly depends on the required analyses since some enzymatic reactions may be influenced past preservatives (Table 2B) (10,26,28). The apply of boric acid affects a number of test strip reactions. This limits the proposed combination of test strip analysis and urine civilisation to obtain an optimal diagnostic test apply. Boric acid keeps urinary pH below 7, prevents dissolution of pus cells (29) and is associated with simulated negative strip exam results (e.grand. protein, white blood cells and ketones). A multi-center report showed a successful preservation of most test strip results as long as 6–24 h (nitrite and glucose were the exceptions) using the preservative-containing BD Plus C&Due south plastic, BD Plus UAP (BD Diagnostics-Preanalytical Systems, Franklin Lakes, NJ, USA) and Greiner Stabilur tubes (Greiner Bio-Ane, Kremsmünster, Austria) (28). Although it cannot be considered as skillful laboratory do, in some laboratories dip slides are put in a urine containing examination tube while using the same sample for other types of analyses. Several reports highlight contamination of the sample by glycine (ii), iodine (30), caffeine (31) and other constituents of the test strip, which leads to unnecessary further investigation. To resolve this problem, urine should exist transferred to the strip instead of immersing the test strip into the specimen. Dipping is only adequate if a dissever aliquot is available.
A detailed table for the correct preservation of 24-hour urine specimens published by the National Commission for Clinical Laboratory Standards (NCCLS) and CLIS is based on the recommendations of the major textbooks and the largest reference clinical laboratories (e.g. Mayo Medical Laboratories). As specimen requirements can be conflicting when a number of tests are required, several different approaches have been proposed ranging from collection of multiple 24-hour specimens to the apply of containers with a two-way divide or three-style split of the preservative. When a 24-hr urine book exceeds the volume of a single container, the urine of two 24-hour containers should be well mixed earlier analysis. It is recommended to regularly cheque the current requirement from reference laboratories as they may change from fourth dimension to time (ten,13,32,33).
Interfering consequence of different urine components on test strip analyses
Due to the presence of alkali metal medication or stale urine, highly buffered alkali metal urine (pH 9) may issue in faux-positive exam strip results for proteinuria. A similar phenomenon is observed (a) if the test strip is left submerged in the urine sample for a as well long time menstruation, (b) if fourth ammonium compounds are used for cleaning the urine containers, (c) if patients are treated with polyvinylpyrrolodione or phenazopyridine, (d) if pare cleansers with chlorhexidine gluconate are used or (e) if blood, vaginal discharge, pus, semen or heavy mucus are contaminating the specimen. Faux-negative results are reported in diluted urine or in the presence of slightly elevated proteinuria other than albuminuria (globulin, immunoglobulin, light chains) (10,34).
At this moment, no urinary components have been associated with imitation-positive glucose oxidase reactions. However, contamination with strong oxidizing cleaning agents peroxide or hydrochloric acid can issue in a false-positive reaction. Using automatic methods for some brands of reagent strips, falsely elevated urinary glucose test strip results tin can also exist caused by elevated urobilinogen concentrations (34). In improver, the temperature can affect the sensitivity of glucose due to its effect on the enzyme reaction. An alkaline pH, a urinary tract infection, an elevated specific gravity and high urinary ascorbate concentrations [oral or parenteral intake of large doses of ascorbic acid or vitamin C (2–fifteen one thousand/day)] may decrease the sensitivity of glucose oxidase (10,35). For that reason the test should be repeated at to the lowest degree i twenty-four hours after the final intake of vitamin C. Using some reagent strips, simulated-negative results have been reported in the presence of moderately loftier ketone concentrations (40 mg/dL) (36).
False-positive reactions for ketones or ketone bodies are seen in (a) urine samples with a low pH and a high specific gravity, in (b) urine containing a loftier amount of levodopa metabolites, (c) in the presence of compounds with sulfhydryl groups (e.chiliad. captopril) or in (d) highly pigmented urine samples (34). An improper storage can lead to false-negative results and beta-hydroxybutyrate is not detected (x,34).
Screening tests for occult blood tin can become faux-positive by (a) certain oxidizing contaminants (hypochlorites when cleaning urine containers or in the presence of bacterial peroxidases by a high bacterial content) (37,38) or by (b) contamination with povidone-iodine (39), (c) menstrual blood, (d) semen or (e) myoglobinuria (34,twoscore). As urine dip-sticks are characterized by a very high sensitivity for intact erythrocytes and free hemoglobin, transient hematuria is a mutual finding. To dominion out transient hematuria, the urinalysis should be repeated on different occasions in asymptomatic patients with a positive dipstick event for hematuria and an otherwise normal urinalysis. If persistently positive results for blood are establish, clinicians should confirm the presence of erythrocytes in urine past a microscopic sediment analysis. A strongly positive dipstick in combination with a non-corresponding negative urine sediment tin exist explained by lysis of erythrocytes and release of free hemoglobin in patients with dilute urine of normal color. The same finding in subjects with grossly bloody urine specimens is suggestive of intravascular hemolysis or rhabdomyolysis (xl). A comment released together with observed (unchanged) dipstick test results pointing to the probable interference could exist informative. In contrast, false-negative results can be found when the examination is delayed, when urine specimens are not well mixed before testing or when using formalin every bit preservative. A lower sensitivity is sometimes seen after the intake of a loftier corporeality of ascorbic acid, later the intake of captopril, in urine samples with a high concentration of proteins or nitrites or with a loftier specific gravity (10,34).
The interpretation of the bilirubin pad is unreliable after the elapse date. False-positive reactions tin can be induced past indican and metabolites of etodolac, by the intake of phenazopyridine or big doses of chlorpromazine or phenazopyridine. A lower sensitivity is observed after the intake of large amounts of ascorbic acrid, in the presence of a loftier nitrite concentration or after the exposure to calorie-free (x,34).
Singular reactions with the urobilinogen pad have been reported past several interferering components: p-aminobenzocic acrid, sulphonamides, paminosalicyclic acrid, phenazopyridine and p-dimethylaminobenzaldehyde. In improver, coloured urine and prophobilinogen can result in simulated-positive reactions. False-negative results can be seen in improperly stored samples (exposure to light) or in the presence of formaldehyde (2 1000/L) or in urine containing nitrite (34).
False-positive results for nitrite are seen afterward a besides long standing at room temperature for several hours or when urine appears red. Urine samples with a loftier concentration of ascorbic acid, with a loftier specific gravity, with a low pH (≤ 6) or with an abnormally loftier urobilinogen concentration volition reduce the test sensitivity (34).
The leukocyte esterase test can give faux-positive reactions due to the use of strong oxidizing agents, formaldehyde (0.4 thou/L) or sodium azide. In addition, coloured urine (bilirubinuria and beet ingestion) can upshot in a positive reaction. Contamination of urine with vaginal belch/fungus or the intake of some drugs (nitrofurantion, clavulanic acid, meropenem and imipenem) tin can lead to mis-interpretation. Vitamin C intake, proteinuria (> 5 g/L), glucosuria (> 20 g/Fifty), 1% boric acid, trypsin inhibitor, oxalate or mercuric salts may decrease the sensitivity of the test (ten,34,41).
The limitations of the detection of leaner by multiple examination strips are the following: coloured urine and in vitro growth can result in false-positive reactions, whereas a short bladder incubation time, Gram-positive bacteria, vitamin C or no intake of vegetables can give imitation-negative results (10).
The relative density/specific gravity can get falsely high in case of proteinuria (> 1 g/L) or the presence of ketoacids. Alkaline metal urine, glucose and urea can decrease the sensitivity of the analysis (10).
Finally, formaldehyde is known to lower the pH; hemoglobin, myoglobin (> 50 mg/L) and ethylenediaminetetraacetic acid (EDTA) have an influence on the creatinine conclusion and the determination of ascorbic acid can become false-positive past similar reducing agents (10).
Particle assay
European urinalysis guidelines (10) have proposed to examine particles < 1 hour afterward voiding at ambience temperature or < iv hours if refrigerated to avoid material lysis. Refrigeration causes a precipitation of phosphates and urates, which may bear on assay of these analytes. Hence, preparing a dissever non-refrigerated aliquot is necessary if differentiation of urinary crystals is requested. Cess of leukocytes gets doubtful when the analysis is performed more 4 hours afterward sampling. However, without adding a preservative, leukocyte preservation can be fairly good even when samples were stored at room temperature for 72 h. These positive results in preserving leukocytes should be interpreted with circumspection, as only samples of adults had been selected (28). In pediatric specimens kept at room temperature, a rapid decrease in the white claret jail cell count was observed (42). Particle lysis accelerates with increasing pH (too long time lag between collection and assay, Proteus sp. infections) (x,25,43,44) and lower relative density (typically seen in young children).
Falsely elevated red claret cell counts measured by menstruum cytometry could exist the result of undissolved powder in the urine container (exam tube) causing a background dissonance signal (28). Morphological erythrocyte analysis remains a separate component of urine particle analysis. Urinary tract and renal diseases tin can be associated with haematuria. However, besides a general bleeding disorder or physiological reasons (e.thousand. strenuous physical exercise) and vaginal contamination (e.g. period), could be the underlying explanation of this miracle. The morphology of urinary erythrocytes may reflect the origin of bleeding: dysmorphic erythrocytes (red cells characterized by an abnormal shape or size), especially acanthocytes or G1 cells (a ring-shaped body with i or more than protruding blebs), betoken toward renal disease. Red claret cells with a normal morphology usually originate from the lower urinary tract (16). A more general apply of this fourth dimension-consuming test is hampered by the lack of unequivocal criteria for identification and quantitation of dysmorphic erythrocytes and the special training (phase contrast microscopy) needed for this examination (45). Morning urine specimens should be preferred as correct evaluation of erythrocyte morphology depends on osmolality and pH (46). An alternative approach to differentiate the bleeding site is based on specific protein analysis, e.thousand. urinary IgG:albumin and alpha-2-macroglobulin: albumin ratios (47).
Manual methods
Several methods have been developed for the detection of urinary elements. In the classical transmission particle assay, the presence of formed elements like ruddy and white blood cells, epithelial cells (squamous and not-squamous epithelial cells), urinary casts (hyaline and cellular), spermatozoa, bacteria, yeasts, various artefacts (eastward.grand. pollen, starch, glass hair, paper, cloth), mucus, lipids and crystals (e.thou. oxalate, carbonate, phosphate, urate and cystine) is checked microscopically (iv,10,48,49). In spite of standardization, intra-assay coefficients of variation of routine sediment assay can go as high as 100%, when rest book of the sediment and centrifugation efficiency are taken into account (4,6,48,50). Hence, a sediment method can never be considered every bit reference of quantitative urinary particle counting (10).
Although centrifugation with removal of supernatant is necessary for sample concentration, it remains a major source of errors. Counting of native urine avoids the errors created past centrifugation; this procedure lowers the belittling sensitivity. In comparison with bacterial cultures, the analytical sensitivity for bacteria is poor at lower counts. The performance figure of bacteriuria depends on the operator's skill, the bacterial species (bacilli or cocci), and on the interference acquired by debris. Centrifugation causes a variable loss of erythrocytes and leukocytes, which does not allow a right quantification. Relative losses due to centrifugation of red and white blood cells vary between 20 and 80% (10).
Mostly, microscopy is used for a rough estimate of the amount of figurated elements. After centrifugation, the specimen analysis can exist performed using glass slides or a counting sleeping accommodation. An reward of using a counting chamber is a larger urine volume that tin be examined, allowing a more precise assay. However, differentiation appears to be easier through a thin liquid moving picture, obtained by a glass slide. Moreover, urine sediment assay using counting chambers is time-consuming. Simple particle differentiation without staining or phase dissimilarity is non enough for renal elements. Much college labor toll are associated with the advantage of a more precise issue. A full-bodied sample using a glass slide is proposed if manual evaluation is requested. Just when carefully working nether standardized conditions, the results tin be related to the original (in vivo) concentration (10).
Standardization of urine sediment examination consisting of urine volume, speed and time of centrifugation, concentration of urine or sediment volume, volume of sediment examined and issue reporting are essential to ensure accuracy and precision of urine microscopic exam. Unless urine samples are investigated inside 4 hours from micturition (at 4 °C) or within 30 min at twenty °C, preservatives should exist added. Although 12 mL is the recommended urine volume for developed patients, a range of five–12 mL urine is acceptable to examine the formed elements in urine. The acceptance of smaller urine specimens and the test protocol is determined by the individual laboratory. A notation on the lab study should be provided to mention each deviation of the standard. A 5-minute centrifugation time at 400 k [RCF, relative centrifugal strength (g) = 1.118 × 10−v × radius (cm) × RPM (revolutions per minute)] preferably at 4 °C is necessary for optimal sediment concentration. The use of the centrifuge brake is contraindicated considering of sample resuspension with decreased numbers of urinary formed elements. The classical manual 12:1 sediment concentration pace is followed by decantation of the supernatant until i mL urine is left, which is gently resuspended. The volume of urine sediment examined is adamant by standardized molded plastic commercial slides and microscopic optical backdrop. Vivid-field microscopy, stage-dissimilarity microscopy or polarized light microscopy are used with depression- and loftier-power magnification. The outcome reporting of a standardized microscope slide arrangement should be supported past written operating procedures, characterized by a universal format, terminology (some components are expressed equally qualitative terms and descriptions for fields of view, other components are enumerated), predefined reference intervals and magnification used for assessment. Finally, traceability of measured quantities and participation in an external quality assessment program are also important (10,51).
Automated methods
Combining sediment microscopy and selective test strip examination of urine helps to assure acceptable specificity and sensitivity of urinalysis (four,45,50). Image assay of native urine specimens was a first technological breakthrough, which allowed analysis of much larger number of particles, resulting in improved results. Still, a lot of expertise was required to identify the different images and substantial staff time was still needed (45,50,52).
Implementation of flow cytometry in the routine urinalysis meant a huge progress in bones urinalysis. In a brusk time menses, using only a small amount of native uncentrifugated urine, a huge amount of erythrocytes, leukocytes and epithelial cells can be evaluated (4). There appears to be a variable loss of these figurated elements in manual methods due to the many intermediate steps involved (centrifugation, decantation and resuspension of the specimen). Moreover, automation allows a better standardization of particle analysis (4,49). In contrast to manual methods, menstruation cytometric assay of casts has an adequate coefficient of variation of 17% (nineteen).
Manual microscopy and flowcytometry prove a good agreement, except for casts and 'yeast-similar' cells, where flow cytometry is inferior. Comparing within run CV'due south for particle analysis between transmission methods, automated microscopy (Iris iQ200, Iris Diagnostics Inc, Chatsworth, Los Angeles, CA, USA) and menstruum cytometry (Sysmex UF-100, Sysmex Corporation, Kobe, Japan) showed that flow cytometry had the best within run CV for erythrocytes, whereas the all-time within run CV for white claret cells was obtained by automatic microscopy (53). In comparing with transmission microscopy, the reproducibility of automatic urine sediment analyzers (LabUMat-UriSed, 77 Elektronika Kft., Republic of hungary and H800-FUS10s100, Dirui Industrial Co. Ltd., Mainland china) was better (8.v–33.3% vs. 4.one–28.5% and 4.7–21.two%, respectively) (54). When counting equal ranges of particles, microscopy is mostly junior to automated methods (fifty,53).
Assay of acute kidney injury proteins
Neutrophil gelatinase associated lipocalin (NGAL) is an emerging biomarker in the diagnosis of astute kidney injury. Withal, urinary tract infection and urinary neutrophil counts affect urinary values of this protein. Urinary leukocyte count correlates with NGAL concentrations: log(Y) (NGAL, μg/L) = 1.284 + 0.439 log(Ten) (urinary white blood cells, x9 cells/L); r = 0.518. In parallel, a correlation between NGAL and the bacterial count has been reported. In leukocyturia or tubular damage (e.g. intensive intendance patients), a mathematical correction has been suggested in cases with pyuria (> 100 × 10nine cells/L) and urinary NGAL concentration > 100 μg/Fifty (55).
Importance of the preanalytical stage in urine toxicology
As virtually drugs are characterized past a predominantly renal excretion, urine is the preferred specimen for cheap, noninvasive and quick substance abuse tests (56). The Clinical and Laboratory Standards Institute (CLSI) developed guidelines concerning specific requirements for the technical performance of urinary drug testing (57). The European Workplace Drug Testing Society (58), the Substance Abuse and Mental Health Services (59), the Swiss Working Group for Drugs of Abuse Testing Guidelines (60), the Joint Technical Committee (61) and the United Kingdom (62) proposed some criteria for urine validity testing based on several parameters: urinary creatinine concentration, specific gravity, nitrite, pH and presence of exogenous or endogenous substances. After checking of the integrity of the sample, positive screening tests are followed by confirmation methods (63).
Information technology should be stressed that an appropriate drove, handling and testing of urine samples are necessary to avert false-positive, false-negative and inconclusive examination results (56). Several specimen tampering methods have been used to avoid detection: substitution of urine by another fluid, adulteration by addition of a strange material, dilution of the urine sample by calculation water. The following countermeasures accept been proposed to forestall deceptive switching or purposeful contamination: (a) placing bluing amanuensis (dye) in the toilet bowl; (b) requesting "photo" identification of the bailiwick; (c) leaving coats, briefcases or purses outside of the collection area; (d) washing and drying hands earlier providing a sample; (eastward) observation of collection; and (f) taking temperature of the urine within four minutes of drove (57).
False-positive results tin can also exist caused by operator errors, cleaning the skin with isopropyl alcohol, contamination of equipment, specimen defoliation, mislabeling and misidentification of the subject, breaks in the chain of custody and errors during the measurement process (57). To subtract the incidence of preanalytical problems, several precautions should be taken into account. An identification and laboratory data system should exist implemented; the condition of seals, shipping cartons, specimen containers and urine specimens should exist checked for integrity; the information on the specimen requisition form and the external concatenation-of-custody form should exist reviewed for completeness and accurateness (57).
Urine toxicology specimens should be stored at a temperature of 2–eight °C for five days, minimizing deterioration and protecting samples from tampering. Storage at ≤ −5 °C is recommended if analysis is postponed for more than than five working days. Also the analysis of medical samples, some additional requirements are prescribed for forensic specimens: (a) storage of the sample in the original container, (b) minimization of the number of freeze/thaw cycles to reduce specimen degradation, (c) use of control measures to ensure specimen integrity and (d) recordkeeping using internal and external chain-of-custody systems (57).
Finally, over-the-counter (OTC) drugs, prescribed medications and some foodstuff, which are chemically related to drugs of abuse, can too be detected by urinary drug tests (56). Amphetamine-related OTC drugs (ephedrine, pseudoephedrine and phenylpropanolamine) are known for their cantankerous-reacting capacities with amphetamines screening immunoassays (64). Fake-positive opiate drug tests have been reported later on poppy food ingestion (65). To reduce cantankerous-reactivity and to increase drug specificity, many drug tests are routinely modified (56).
Preanalytical aspects of urine metabolomics
The monitoring of the impact of the preanalytical steps on urine sample quality and stability tin exist fulfilled past 1H NMR metabolic profiling. Standard operating procedures (SOPs) for deposition in biobanks have been proposed (66). Stability of the urine metabolic profile at various storage temperatures was studied for different preanalytical treatments (prestorage centrifugation, filtration and addition of sodium azide). According to the European Consensus Adept Group Report (67), biobanking procedures for urine should consider the following recommendations: (i) cells and particulate matter should be removed; (ii) storage of specimens at a temperature of −80 °C or lower; (iii) time limits for processing should be experimentally defined; (four) specimens should be stored without additives, unless specified for a particular downstream assay.
Is in that location an influence of centrifugation on assay results?
To avoid the presence of components affecting the spectral quality, standard protocols (68) for NMR analysis of urine samples crave a centrifugation at 14,000 Relative Centrifugal Force (RCF) (5 min, 4 °C). A loftier speed may crusade devastation of cells and a release of cellular components, affecting the NMR contour. The virtually distant from nonprecentrifuged samples are the samples precentrifuged at a speed in the 1,000–iii,000 RCF range, while samples precentrifuged at eleven,000 RCF are slightly closer to the aliquots that do not undergo any precentrifugation. If a mild precentrifugation (1,000–iii,000 RCF) is practical, cellular components are spun down. The subsequent 14,000 RCF centrifugation of the supernatant is useful for elimination of suspended particles. Precentrifuged or non-precentrifuged samples show differences in metabolic profile, which are owing to chemical shift changes. Soluble components released by cells in fresh urine may alter the physiochemical properties of the solution. Presence of cellular components affects NMR profiles fifty-fifty if non-fresh samples are analysed. NMR metabolic profiles of samples that have undergone a balmy (RCF between 600 and 2,500) precentrifugation earlier freezing at −80 °C differ from non-precentrifuged samples stored for seven days at the aforementioned temperature. This outcome is less pronounced after storage in liquid nitrogen.
Which is the preferable preservation method?
The two most commonly used preservation methods have been compared: addition of sodium azide and the use of filtration (69) with or without a precentrifugation step. Spectral variations were followed later on urine processing or thawing. pH-sensitive metabolites undergoing chemical shift variations show changes over time. Sample alkalinisation is consequent with shift variations for the He1 Northward-methylhistidine; also, changes in the chemic shifts of the resonances of xantine are observed with time. For some molecules, concentration changes are observed: whereas an increment of succinate and acetate are reported with fourth dimension, glutamate/glutamine, urea and lactate concentrations decrease. Filtration stabilizes NMR spectra over time.
What are the recommendations?
The origin of changes that affect the NMR spectra tin be the issue of a combination of chemical reactions, bacterial growth and enzymatic activities of urine. For maintaining the original urine metabolome, the post-obit procedures for optimal processing and direction have been proposed: (i) the combined utilize of a mild pre-centrifugation (RCF between 1,000 and 3,000 at four °C) and filtration should remove cells and particulate matters; (ii) samples should be stored long-term in liquid nitrogen to avoid destruction of rest cells; (iii) fast processing; (iv) storage at iv°C betwixt collection and processing. Add-on of additives is to be avoided since the required concentrations volition generate NMR signals covering the resonance of metabolites and may impact the original NMR profiles. For the maintenance of the metabolome, time between collection and processing and the temperature at which urine specimens are kept during this time delay should exist reduced (68).
Optimal urine quality direction in a routine clinical laboratory
To improve the optimal urine quality management in routine clinical laboratories, the CLSI develops best practices in clinical and laboratory testing past using a core set of "quality system essentials" and promotes the use of these standards worldwide (thirteen). Also, the International Standards Organization (ISO) certificate 15189:2007 lists particular requirements for quality and competence (70). Looking at the most contempo CLSI recommendations, information technology is stated that high quality urine samples can merely be delivered by appropriate urine collection tubes (fabricated of clear plastic and with conical bases for microscopic assay of urine sediment) and leak-proof containers. In improver, loftier quality pipettes and standardized microscope slides with calibrated volumes for analysis of urine sediment are essential. A 2d important preanalytical signal is whether preservatives are used or not, as unpreserved samples can requite rising to bacterial proliferation. Refrigeration for storage or transportation should always be followed by equilibration to room temperature and well mixing earlier analysis. Several drugs can disturb the examination results of urinalysis, which implies that a 'drug-free" specimen tin can simply be achieved by temporary cessation of a particular medication. Besides the influence of clarity and colour of the urine samples, a number of substances tin can interfere with dipstick tests, co-ordinate to the type of test strip. In comparing with random urine testing, the examination of chemic analytes is more reliable when timed sampling is used, which is all the same decumbent to pre-analytical errors. Microbiological cultures and antibiotic susceptibility testing tin be influenced past contamination, defined as the presence of more than 10,000 CFU/mL of two or more than organisms. Random urine samples have a higher contamination adventure in comparison with midstream clean take hold of samples. False-positive results can also be caused by bacterial overgrowth due to delays in the transport of samples. Treatment with antibiotics prior to urine sampling can atomic number 82 to simulated-negative reports.
Summary
Urinalysis plays a key function as an assistance in the differential diagnosis of many renal and urologic diseases. The preanalytical phase, including biological collection, identification, storage and specimen send, preparation for analyses of the specimen (east.m. centrifugation, freezing, thawing, aliquoting and sampling) largely determines the analytical process and the over-all quality. For that reason nosotros take presented guidelines for a correct preanalytical management of urine samples in a flowchart (Figure one).
Flowchart illustrating the guidelines for a right preanalytical management of urine samples.
As urine samples are often collected by patients themselves, the analysis of urine is one of the most susceptible examinations to preanalytical issues. In addition to the insurance of right sampling, the clinical lab should optimize send and sample preservation. Next to the employ of a primary urine container, it is recommended to divide the original urine sample into various smaller aliquots for morphological, microbiological and chemical analyses, decreasing the risk of contamination. Implementation of vacuum systems has enabled swift transport of urine specimens and limits the risk of contamination and errors. The disruptive strength generated past the vacuum on breakable figurated elements (eastward.g. casts) is mostly underestimated and insufficiently examined.
Equally modernistic urinalysis (catamenia cytometry, automatic microscopy) is characterized by a low CV, preanalytical aspects of urinalysis are of growing importance. Special attention should be paid to casts, the most breakable structures in sediment analysis. There is a call for novel studies to optimize the analysis of urine sediment. The investigation of dysmorphic erythrocytes, in item acanthocytes, is too important in the diagnosis of glomerular disorders. The analysis of urine sediment cannot however be abandoned in the 21st century.
The time lag between voiding and examination of urine is a limiting factor for the over-all diagnostic accuracy. No preservatives are needed for many chemic analytes examined with test strips, if the sample is refrigerated and the analysis tin can be performed inside 24 hours. If a filibuster cannot be avoided and refrigeration is not possible, urine containers prefilled with preservative (boric acid alone or in combination with formate or other stabilizers) may be used. Since in everyday routine, near of the clinical laboratories are receiving urine samples with delays of several hours, we recommend to employ refrigeration as a preservative instead of chemical preservatives for urinalysis according to the guidelines of the NCCLS (xiii). If commercially available preservatives are used, their influence on chemical properties and appearance of particles should be kept in mind. Ideally, preservatives are present in a lyophilized form. An important interference of preservatives with several chemical assays has been demonstrated. Virtually urine preservatives were originally simply intended for preventing bacterial growth and not to perform chemic analysis or particle counting. The combined use of test strip analysis and particle analysis (manual or automated) as a first step before bacteriological analysis has been proposed by guidelines in different algorithms to assure efficient use of resources (4). As in that location is currently no preservative that is able to stabilize urine for chemical and particle analysis, novel enquiry projects are needed. Until the evolution of such a preservative, clinical labs need to gear up two aliquots. Only a preservative stabilizing both bacteria and urinary particles can be considered as a valid culling for sample refrigeration. As urine metabolomics has become a hot topic, the European Consensus Expert Group Study has published a number of recommendations for biobanking procedures (67).
Table 2b.
Influence of preservatives on examination strip reactions.
| Analyte | Boric acid | Formaldehyde | Hg salts | Chloral hexidine |
|---|---|---|---|---|
| Ruby blood cells | ||||
| White blood cells | ||||
| Proteins | ||||
| Glucose | ||||
| pH | ||||
| Leaner |
Footnotes
Potential conflict of interest
None declared.
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