It is no secret that urinalysis has been a bit behind in terms of technological advancements, remaining largely unchanged since its early days. This could be set to change. New parameters and new clinical applications could be introduced to the market as study evidence builds to support the routine clinical use of urinary biomarkers. In the meantime, advances in automated urine sediment analysis could provide benefits to clinicians that were previously only seen with traditional manual microscopy, bridging the gap between the old and the new, and bringing urinalysis back into the spotlight.

The global urinalysis market size stood at USD 1.37 billion in 2015 and is expected to reach over USD 2.14 billion by 2022, predicts Grand View Research. The introduction of CLIA-waived urine reagent strips such as CLIA-URS-10, CLIA-URS-10-3PROMO, and CLIA-URS-10-10 provide for an effective screening tool for rapid testing in urine analysis, which are estimated to enhance the usage rates of urinalysis reagents, thus accentuating the urinalysis market growth over the next 7 years.

Automation is a key technological advancement affecting the efficiency and accuracy delivered by the new-generation urinalysis devices and hence, the persistent demand for novel urinalysis instruments and consumables. For instance, the automatic bench-top and portable biochemical urine analyzers, automated urine sediment analyzers, and automated microscopic urine analyzers are the next-generation, advanced instruments anticipated to foster the urinalysis market growth.

The target population base for urinalysis market is increasing owing to, factors such as the rising prevalence of target diseases, misdiagnosis, and low awareness levels pertaining to urine analysis in low-income countries. High incidences of obesity coupled with hypertension, diabetes, and other chronic disorders foster the growth of the urinalysis market.

Urinalysis Renaissance

Decades ago, urinalysis was an important tool in the clinical diagnostic toolkit, and it was widely understood to provide the clinician a wealth of information on a patient's condition. With the advent of newer, more descriptive, and more specific serum tes ts and methodologies, the focus on urinalysis has slipped away, along with precious capital budget funds and educational focus. But the underappreciated discipline just might be primed for a resurgence of sorts, and, as more attention is paid to the quality of test results obtained and the resulting impact on patient care, the oldest form of clinical testing could still offer advances to improve patient care.

The last major change to the urinalysis testing model was the automation of urine sediment analysis and the associated reduction in the need to perform the tedious, messy, and time-consuming manual microscopic review. This shift was mandated in part by the first wave of experienced medical technologists hitting retirement age, leaving the lab, and taking away years of clinical microscopy experience with them. New medical technology graduates, raised on automation and computers and with comparatively little exposure to traditional manual methods, welcomed the new and easier way of performing urine sediment testing that virtually eliminated the need for the old-school manual slide review. For nephrologists, urologists, and other clinicians, CLIA regulations restricted the ability to perform microscopic urine sediment analysis outside of clinical laboratories, so their ability to accurately read and interpret urine sediment findings waned as well.

To compensate for this decline in skillsets, the nephrology community began researching a renal troponin, i.e., the biomarker(s) that would help clinicians quickly and more accurately diagnose kidney disease. While research has uncovered some unique biomarkers with great potential -
KIM-1 (kidney injury molecule 1), Cystatin-C, NGAL (neutrophil gelatinase associated lipocalin) and others - the markers do not always provide a consistent indication of the origin of the injury, so abnormal results can point to a range of conditions. Because of this, the medical community has yet to adopt any one marker as the acute kidney injury (AKI) marker of choice.

Any urinary biomarker assay developed for the market should be easy and inexpensive to perform, and not subject to interference from other urinary chemistries.

When viewed this way, it is not a stretch to say that an effective urinary biomarker is already available to clinicians in the form of urine sediment analysis. When combined with urine test strip chemistry results, it can provide information on the kidney structures (glomerulus or tubules) directly affected by disease.

To date, with automated methods, elements in the urine sediment have been reported only as flags, with operator follow-up required before the final result is released. Nephrology literature suggests that a urine sediment score consisting of the number of renal tubular epithelial cells per high-power field and granular casts per low-power field can be used to differentiate hospital-acquired AKI from acute tubular necrosis (ATN) and acute renal failure caused by a sudden reduction in blood flow to the kidney (pre-renal AKI). A urine sediment score of ≥2 has a positive predictive value of 100 percent for ATN. A score of ≥3 can be an indication of worsening AKI and probable patient mortality.

Way Forward

In a few years - or perhaps more than a few, but in the foreseeable future - urine may again become the specimen of choice for detecting cancer and other diseases with a genetic component, with the next generation of urinalysis analyzers looking more like their immunoassay or chemistry cousins than the traditional urinalysis platform. New parameters and new clinical applications could be introduced to the market as study evidence builds to support the routine clinical use of urinary biomarkers. In the meantime, advances in automated urine sediment analysis could provide benefits to clinicians that were previously only seen with traditional manual microscopy, bridging the gap between the old and the new and bringing urinalysis back into the spotlight.

Lyon Xie, Vice General Manager-International Sales & Marketing,Dirui Industrial Co. Ltd.
Industry Speak
Development of Urine Formed Elements Analysis

There are many reasons that can cause kidney diseases, and urine is a direct indicator of the renal condition. So in the clinical laboratories, urinalysis though a small sector, is one of the most commonly performed tests. There are three parts - the physical tests (color, turbidity and specific gravity), the dry chemistry analysis, and the urine formed elements analysis. Formed elements analysis is the core. It can detect casts, crystals, epithelial cells, and sperm which cannot be detected by dry chemistry and in addition the RBC and WBC results can correct the possible false-negative or false-positive of dry chemistry results. For instance, dry chemistry pad detects neutrophil and monocyte but no other WBC cell. When there are rejection reactions in a renal transplant case or other diseases causing lymphocyte urine, the main WBC cells in the urine are lymphocytes. Urine formed elements analysis can detect the lymphocytes rather than the dry chemistry.

Urine formed elements have a wide variety and forms, which are easily damaged or changed by forms. It requires experience of years to do the analysis and mainly a classic manual microscope. This procedure lasting for more than 200 years is still considered the gold standard.

However, there are problems in manual examination. The results given by different laboratories or different examiners vary hugely. A well-trained, experienced, professional team is required for manual examination to realize accurate interpretation. The experiment procedure, especially before the analysis, is quite complex. It is labor-intensive, time-consuming, and there are interferences in many steps. There is no standardization or control of human eye. Results are easily affected by subjective factors.

Nowadays, with increasing numbers of urine samples, manual examination cannot solve the contradiction between supply and demand. The automation of both dry chemistry and formed elements is the final solution for labs. Automatic analyzers can improve standardization and accuracy, and free the lab staff from the time-consuming manual work.

The automation of formed elements started quite late, dating back to 1980s. There are now many companies globally, manufacturing all kinds of analyzers, some appearing as stand-alone analyzers but most connecting to dry chemistry analyzers. And in recent years, with creativity, urine formed elements analyzers and urine dry chemistry analyzers are combined to form a compact whole, called hybrid.

Talking about urine formed elements automation techniques, there are three types - flow cytometry technique, flow cytometry digital imaging technique, and static digital imaging technique.

Flow cytometry technique. Semi-conductor laser sheath and nucleic acid fluorescent staining are used together to do the measurement. The results are displayed as scattergrams.

Flow cytometry digital imaging technique. Un-centrifuged urine sample wrapped by the sheath flows by the digital imaging device and the images are captured during the movement of the flow of sample and sheath for software evaluation.

Static digital imaging technique. Urine sample flows into the counting plate or cuvette of various specifications and settles down at the bottom by physical method or is kept still, and then images are captured through microscopes of different power lenses in the static state for evaluation.

Given the wide variety and changeability of the formed elements, image identification, no matter manually or automatically, is still the first choice. With automation, convenience, efficiency, and standardization can be guaranteed. It can screen out a large number of normal samples. The review rate with microscope can be reduced to 10-40 percent depending on different principles of analyzers and different routine practices in labs. The automatic analyzer still cannot replace the manual microscopic examination, but with the expansion of the database, there is every reason to believe the day would finally come when the database would be infinitely big.

Lyon Xie
Vice General Manager-International Sales & Marketing,
Dirui Industrial Co. Ltd.

Dr Neena Verma, Chief Pathologist, SRL Limited, Fortis Hospital, Noida
Second Opinion
Automated Urine Analyzers

Urine examination is a powerful non-invasive tool for the diagnosis of many conditions especially diabetes and urinary tract diseases, detecting them even before the patient becomes symptomatic. Urine comprises almost 30 percent of all samples received in a laboratory.

Technology Trends. Urine has been analyzed since time immemorial but the methodology has undergone a sea change. In ancient times, only the physical properties were evaluated by inspection, smelling, and even tasting. Chemical tests were added later. Till the 20th century, a separate test was done for each chemical analyte. Microscopy was added after the invention of the microscope. Thus, a seemingly simple urine examination was a laborious procedure taking at least 30-45 min per sample. The commercialization of dipsticks for urine analysis in 1956 simplified it tremendously as all chemical analytes and specific gravity could be detected within a minute by dipping the strip into the urine sample.

The first automated urine strip reader allowed partial automation of urine examination in 1972. Microscopy still had to be performed manually. This is tedious and time-consuming as each urine sample is centrifuged and the resultant sediment is microscopically examined taking 10-15 min per sample.

Application of automated microscopy with digital imaging and flow cytometry to urine particle analysis in this century has revolutionized urine analysis. Now urine analysis can be completely automated. This has markedly reduced turnaround times, risk of contamination to staff, manpower and consumable costs, also eliminating clerical errors while producing standardized reports.

Challenges. Automated urine sediment analyzers pick up WBCs, RBCs epithelial cells, bacteria, crystals, and casts. However, folded epithelial cells, dysmorphic RBCs, and trichomonas may be missed. Yeasts may get confused with RBCs. Crystals and casts cannot be accurately sub-classified. Confirmation by manual microscopy is still required for pathological urine sediments. However, majority of the normal urine samples can be screened and the lab's burden of manual microscopy can be greatly reduced.

Future trends. Opportunities exist for better software designed to correctly identify formed elements and bacteria in urine. In future, urine analyzers may even be able to identify microorganisms in the same centrifuged pellet, markedly reducing the waiting time for culture reports. This is being studied by integrating matrix-assisted laser desorption ionization-time of flight mass spectroscopy 
(MALDI-TOF MS) with the urine analyzers.

Dr Neena Verma
Chief Pathologist,
SRL Limited, Fortis Hospital, Noida

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