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Technology advances pave the way for urinalysis

With the advances in today’s technologies, urinalysis has great potential, and the merging of test strip technologies with smartphone technologies can lead to tremendous changes and deeply integrate point-of-care testing into the health system.

There is an unmet need for a transformation in healthcare from reactive and hospital-centered care to a more proactive approach, encompassing preventive, evidence-based, and person-centered care. The focus must shift from disease to well-being. To support this much-needed transformation, there is an imminent demand for low-cost, compact, and transformative technologies to perform hourly, daily, or continuous health measurements across the population. Only rigorous scientific innovation can realize such next-generation technologies, which promise to improve patients’ well-being, decrease the cost of care, and take on ever-present medical challenges.

New technological advances have paved the way for significant progress in automated urinalysis. Quantitative reading of urinary test strips using reflectometry has become possible, while complementary metal oxide semiconductor (CMOS) technology has enhanced analytical sensitivity, and shown promise in microalbuminuria testing. Microscopy-based urine particle analysis has greatly progressed over the past decades, enabling high throughput in clinical laboratories.

Urinary flow cytometry is an alternative for automated microscopy, and more thorough analysis of flow cytometric data has enabled rapid differentiation of urinary microorganisms. Integration of dilution parameters (e.g., creatinine, specific gravity, and conductivity) in urine test strip readers and urine particle flow cytometers enables correction for urinary dilution, which improves result interpretation. Automated urinalysis can be used for urinary tract screening and for diagnosing and monitoring a broad variety of nephrological and urological conditions; newer applications show promising results for early detection of urothelial cancer. Concomitantly, the introduction of matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) has enabled fast identification of urinary pathogens. Automation and workflow simplification have led to mechanical integration of test strip readers and particle analysis in urinalysis. As the information obtained by urinalysis is complex, the introduction of expert systems may further reduce analytical errors, and improve the quality of sediment and test strip analysis. With the introduction of laboratory-on-a-chip approaches and the use of microfluidics, new affordable applications for quantitative urinalysis and readout on cell phones may become available.

Technological advances
Urinalysis has been a useful diagnostic tool since thousands of years. Although urine was the first body fluid to be examined by mankind for the diagnosis of diseases, it is still one of the most common specimens used in clinical and diagnostic laboratories. New technological advances have paved the way for significant progress in automated urinalysis. Time and accuracy are the two key factors for diagnosis. In UTIs, urine dipsticks are very fast and easy to use, but it lacks the accuracy, whereas on the other hand, urine culture for antimicrobial susceptibility testing shows clinically reliable and accurate results, but it takes up to 3 days to give results.

Many novel and improved diagnostic technologies and tools are introduced in the market, and some of them are already approved for clinical use and help significantly in increasing the accuracy and decreasing the time of the test; a good example would be nucleic acid tests and mass spectrometry. Some other technologies show promising future like the utilization of smartphone for urinalysis.

Test strip technology. Major improvement in the test strip technology has been made in recent years. Not only are highly sensitive test strips being introduced, but also, now one can find strips, which give quantitative results for urinary proteins.

The financial aspect is also of great importance, especially in the Third World and developing countries; inexpensive test strips for various diagnostic reasons such as the diagnosis of diabetes from urine sample are available. Test strip method also shows promising results in antibiotic susceptibility tests; if optimum diagnostic requirement is reached, it can reduce the test time significantly from 2 to 3 days to few hours.

Automated microscopy. Urine microscopy is one of the most important diagnostic methods for UTIs and other kidney diseases. Manual microscopy is time-consuming and can be labor-extensive. Furthermore, with centrifugation, decantation and re-suspension always lead to cell loss and cellular lysis. With the current available digital microscopy technologies, a significant time reduction can be archived with much more sample being processed in significantly shorter time in comparison to manual microscopy.

In addition, with the ability to process uncentrifuged urine sample, issues like cell loss and lysis are of no more concern. Many automated analyzers are now available in the market with different kinds of technologies like laminar flow digital imaging technology and pattern recognition technology.

MALDI-TOF. The proteomic method, matrix-assisted laser desorption ionization–time-of-flight mass spectrometry (MALDI-TOF MS) for identification of microorganisms directly from culture, coupled with gram stain, has given new direction, saved considerable amount of time in diagnosis of UTI, and contributed greatly in the field of clinical microbiology in general.

It can identify different pathogens accurately and significantly in a short time. The utilization of this technology for the diagnosis of UTIs and furthermore in preforming antibiotic susceptibility tests to decrease the testing time from days to as fast as 2 hours can open wide doors.

Urinalysis and smartphones. Smartphone technologies improved the quality of life in countless fronts, and it has large potential for applications in the medical field. With PoC testing attracting much attention in recent years, smartphone solutions can be a valuable tool in this regard. It can, for example, increase the compliance of populations with screening programs by offering easy and fast screening method. Studies exploring the possibility of establishing a smartphone-based diagnostic platform for rapid detection of Zika, chikungunya, and dengue viruses showed valuable prospects. Several other smartphone applications utilizing urinalysis for various diagnostic reasons have been tested and look promising, which can greatly help medical practitioners and patients alike.

Flow cytometry. Flow cytometry is being introduced as a reliable method for fast diagnosis of UTIs by counting the bacteria in the urine specimen. With the improved counting precision over visual counting methods, highly accurate results can be obtained by this method. Detection of bacteriuria can be achieved with clinical standards, using flow cytometry technology.

Immunochromatographic test strips. Lateral flow immunochromatographic assay (LFIA) strips are often used for the detection of proteins and hormones. Escherichia coli and Neisseria gonorrhoeae have been detected by mie scattering as indicator of sexually transmitted infections. The LFIA method is based on the ELISA, which is considered the gold standard in protein detection. The ELISA relies on captured antibodies to concentrate the target molecule, and a labeled secondary antibody binds the captured targets. The concentration of target molecules is determined by a measurement of the rate of color development, fluorescence generated, or magnetic field, depending on the label used.

The LFIA typically uses antibodies deposited in lines along a test strip. The test strip has a higher detection limit compared to the ELISA. A chemiluminescent LFIA design has been produced for the measurement of serum albumin. Light is generated as a result of a reaction catalyzed by horseradish peroxidase (HRP), concentrated at the test and control lines to be detected by a photodiode. Enzyme multiplied immunoassay technique (EMIT) relies on the use of an antigen, linked to an enzyme that competes with the target analyte for binding sites.

The enzyme is inactivated by binding and enzyme activity can be monitored as a measure of target concentration. Devices are available for the detection of drugs, using EMIT. Multiplexed lateral flow tests are being developed to improve the utility of portable test strips.

Portable reagent strip readers. Reagent strip readers are an effective way to objectively assess colorimetric test strips. They can be designed to read fluorescent tags and could work with cell phone cameras, making them particularly useful for diagnosis in low-resource settings. Rapid improvements in the quality of smartphone cameras and image processing techniques have enabled low-cost devices for quantifying colorimetric test strips. Recently, there has been a significant interest in the development of portable urinalysis reagent strip readers for PoC testing applications.

Second Opinion

No more just a urine routine

Dr Anupa Dixit
Lab Director,
Subarban Diagnostics

Urinalysis is a major diagnostic screening test in the clinical laboratory, with an important role in diagnosing and monitoring nephrological and urological conditions. Laboratory medicine began with the analysis of human urine, which was called uroscopy till the 17th century and today is termed as urinalysis. Out of all the analyses performed in the clinical laboratory the urinalysis has one very distinct advantage – it is completely non-invasive!

Urinalysis in India
Until the last decade, semi/automated urine chemistry and manual microscopic urine sediment analysis was the only available and widely accepted urinalysis methodology in India. However, manual microscopic sediment examination is labor-intensive, time-consuming, and lacks standardization in moderate and high-volume laboratories. In addition to these limitations, one important factor is centrifugation loss (unsettled urine particles thrown out in supernatant after centrifugation), which is ignored in the manual sediment analysis process. Still, this methodology is practiced in more than 90 percent of laboratories in India.

Automation in urinalysis
Automated technologies and informatics have greatly reduced the labor intensity of urinalysis, and have paved the way for significant progress in urinalysis with better accuracy and precision.

In urine chemical analysis, quantitative reading of urinary test strips, using reflectometry, has further improved using complementary metal oxide semiconductor (CMOS) technology, which has enhanced analytical sensitivity and quality of results. Microscopy-based urine particle analysis has greatly progressed over the past decades, enabling high throughput in clinical laboratories. Urinary flow cytometry is an advanced alternative for automated microscopy. More thorough analysis of flow cytometric data has enabled rapid differentiation of urinary cells, and formed elements with many additional parameters and value-added information and flags.

In addition to UTI flagging, RBC morphology, and bacteria class information, flow cytometry-based urine sediment analyzers provide urinary dilution parameters, namely, conductivity and osmolality, which further improves result interpretation along with specific gravity obtained from urine test strip readers. In a nutshell, automation brings standardization to the whole process and reliability and confidence to report urinalysis results.

Our experience with urinalysis automation
Being an NABL- and CAP-accredited patient-centric large diagnostics center, we had embraced complete urinalysis automation seven years ago. Automated urine analyzer, based on fluorescence flowcytometry, has improved count precision and accuracy, compared with the traditional methodology, with significant reduction in labor and TAT. This is in line with our fundamental mission to propagate healthier living for all of our patients.

The road ahead
The current challenges facing urinalysis may be overcome with the development of high-throughput integrated sensing systems, and PoC devices for personalized medicine. Measurements right at the site of collection reduces the need for sample storage and transportation for testing and may provide more reliable results for patients sending samples far from testing facilities.

The results may be available shortly after sample collection, enabling more rapid response to results. Additionally, samples may be screened at the site of collection to determine if a more detailed analysis is required to reduce the number of samples sent to testing facilities, reducing the demand and cost of urinalysis testing. By screening for infections and monitoring chronic diseases before they become symptomatic, the demand on testing labs may be reduced and potential for early intervention may be improved.

The contents of urine samples are highly variable, among individuals and for a given individual over time. Remotely monitoring contents of urine samples over time provides an opportunity to establish normal baselines for individual users. Trends in results over time may be used to identify the development of health challenges before symptoms appear.

Integration of new functional components in microfluidic devices like pumps, mixers, valves, and filters may be used to enable automated sample handling, processing, analysis, and disposal, in order to overcome the need for trained technicians to perform analysis. Additionally, many studies focus on validating methods on healthy subjects. Work should be done to investigate the reliability of these methods on subjects with health issues, and to identify behaviors that influence test results.

Continuing development of microfluidic detection methods for the analysis of urine will lead to reliable sensing modules for many diagnostic indicators. Many of these sensing modules may be integrated in a single device to allow for the simultaneous detection of several analytes.

The development of new microfluidic microscopies and lensless imaging techniques provide an opportunity to dramatically reduce the size and cost of microscopic examination of samples. High-throughput microfluidic microscopy has the potential to detect infections with low concentrations of bacteria without long incubation times, significantly reducing the time for test results.

PoC diagnostic devices may be developed that are capable of continuously monitoring urine samples on an ongoing basis, enabling the early detection of diseases and the monitoring of chronic diseases. These monitoring devices may be portable units to be deployed, or permanently installed in the home such as smart toilets. Most of the new PoC urinalysis devices are based on reagent strip readers. The reagent strip design has inspired several chip-based sensors employing a wide range of detection methods.

It is not recommended that one should simply develop more test strips to cover a wider range of analytes or concentrations owing to the complex nature of the sample and the interactions among different components. Making a device that incorporates redundancy by measuring several parameters using independent methods may provide more reliable information about sample contents. Not all of the methods used in urinalysis testing need to be translated into microfluidic devices.

There are several methods that can be used to detect the presence of bacterial infection. More extensive testing can be performed in lab settings to identify the infecting organism and to determine an effective antibiotic treatment for the infection.

As the methods used to perform urinalysis continue to translate into portable PoC monitoring devices, results can be obtained directly from the site of collection, rapidly, and on a continuing basis. The integration of urinalysis devices into smart toilets also allows monitoring of the frequency of urination and volume of urine.

This provides an opportunity to detect developing illnesses at an early stage, as well as to monitor ongoing chronic illnesses and response to treatment. The personalized urinalysis may be used to reduce the number of samples sent to large testing facilities to save time and cost by prescreening samples. With the development of lensless imaging devices, automated PoC microscopy may also be conducted on urine samples for direct detection of sediment and infectious particles.

These sensing strategies may also be applied to alternative remote fluid monitoring applications such as analysis of saliva, environmental water quality monitoring, and process control.

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