In the words of Prof Alexander Fleming, although he discovered penicillin on the morning of 28 September, 1928, even 14 years after this groundbreaking discovery, he was still experimenting to investigate the effect of the drug on bacteria. In his Nobel Lecture in 1945, he was already warning of the effects of bacteria getting resistant to the new drug. This is now one of the biggest challenges facing medicine today. Fleming was aware of the possibility of bacterial resistance and his expectations about the emergence of resistance to antimicrobial agents became a real fact because of use and misuse of antibiotics, which developed now to a global public health problem. This is even more of a problem as many bacteria today are becoming resistant to antibiotics at a faster rate than science is able to develop new antibiotics.

Over the past 25 years, the bacteria Mycobacterium tuberculosis, Staphylococcus aureus and Escherichia coli, among many others, have begun to show a resistance to antibiotics, a situation that threatens global public health. According to David Payne, head of Glaxo Smith Kline’s (GSK) antibacterial discovery performance unit, says, “There are documented cases where people have infections caused by bacteria that are resistant to all the available antibiotics and the mortality in those patients is very high”.

According to Aly and Balkhy, in an article published in 2012 in the journal “Antimicrobial Resistance and Infection Control” about the prevalence of antimicrobial resistance in clinical isolates from Gulf Cooperation Council countries (GCC), they reported that within 20 years (1990-2011) E. coli and Klebsiella pneumonia were the most prevalent reported microorganisms by GCC countries with resistance data.
 
According to the 2014 Review on Antimicrobial Resistance, chaired by Jim O’Neill, former Goldman Sachs chief economist and UK government Treasury minister, if antibiotic resistance is allowed to increase at its current rate, it is projected to cause up to 10 million deaths a year globally by 2050. Later, and according to the 2016 report by the Review of Antimicrobial Resistance, also chaired by O’Neill, there are now an estimated 700,000 deaths worldwide from drug-resistant infections. About 50,000 of them are in Europe and the US.

As there are no simple solutions to microbial resistance to antimicrobial agents, it was heartening that MEDLAB 2018 as part of its strategy to spread awareness about this global challenge organised a conference titled ‘Antibiotic Use and Misuse’. The conference was a highly anticipated new MEDLAB track that featured engaging expert-led sessions aiming to address the challenges currently being faced concerning antibiotic use within the region, and globally. The conference brought together a group of scientists dedicated to understanding and overcoming the use and misuse of antibiotics. The conference fostered the sharing of ideas between investigators at the forefront of their field as well specialists, in both speaker sessions and panel discussions. Alongside this, the event discussed the latest developments, innovations, and the corrections necessary to meet the critical need of tackling antibiotic misuse as investigators and experts presented their research and promoted applications of results and resources.

Participants convened at the Dubai International Convention and Exhibition Centre, Dubai, UAE on February 8, 2018 to: (1) Review the key and current national and global approaches to antibiotic use enabling sustainable, effective and appropriate use of antimicrobial agents; (2) Recognise both emerging and reemerging resistant pathogens to increase awareness and improve handling of antibiotics; (3) Discover advanced infection control methods and alternatives to antibiotics in infection management to help reduce antimicrobial resistance in the region; (4) Evaluate antimicrobial stewardship efforts to advocate for better practice in regional healthcare establishments; and (5) Analyse the main challenges concerning antibiotic use and misuse within the region to better tackle these obstacles and to enable best practices in preventing microbial resistance.

Covering an extensive range of topics, specialists were not only guaranteed to be educated and bridge gaps in knowledge, but also had an unparalleled opportunity to liaise with the leaders in the field. The different expert presentations and panel discussions of the conference were targeted towards fulfilling the broad objectives as follows:

1. The National and Global Approaches to Antibiotic Use and Misuse: Dr Ursula Theuretzbacher from the Center for Anti-Infective Agents, Vienna, Austria, ESCMID, Basel- Switzerland presented the international approach along with her experience on the strategies to improve the use of antibiotics and their effectiveness, the need for reducing the potential for emergence of resistance, and the latest updates and review of antibiotic research and development. Dr Theuretzbacher pointed out that the overuse and unnecessary use of antimicrobials for humans and animals promote the development and spread of resistance. Much of the use of antibiotics in the world is for animals rather than humans and that much of this is for promoting the growth of animals rather than treating sick animals. On the other side, Dr Khuloud Bin Rafeea from Pharmacy Department, Tawam Hospital, Al Ain, UAE presented the national exercise as represented by Tawam Hospital, Al Ain, UAE on developing, implementing and measuring the value of hospital antimicrobial stewardship programmes. At the end of this session, Dr Stefan Weber from Sheikh Khalifa Medical City, Abu Dhabi, UAE, discussed the guide for effective stewardship programmes in ICU, the hospital and the community.
2. The Updates on Resistance and Emerging and Re-emerging Pathogens: In this session, Dr Jens Thomsen from Department of Health, Abu Dhabi, UAE compared the national and regional patterns and resistance trends, epidemiology and surveillance of antimicrobial resistance. Dr Thomsen stressed the importance of establishing a database in the Middle East & North Africa (MENA) region for antimicrobial resistance surveillance. The challenge of resistance in Gram negative and positive bacteria was highlighted by two experts: Dr Adnan Alatoom from Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE, who updated the conference with the molecular reasons of Gram negative pathogens’ resistance, and by Dr Atef M Shibl from Al Faisal University, Riyadh, KSA, who addressed the association of the misuse of antibiotics with the wrong diagnosis or lack of rapid diagnostics of the kind of disease affecting patients along with the exposure of microbes to a broad-spectrum of drugs that may or may not cure the patient, thus increasing the likelihood of developing resistance of these drugs.
3. Advancing Infection Control: In this session, Dr Abiola Senok from Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE, moderated a panel discussion on the national, regional, and international experience on the alternatives to antibiotics in infection management. Three experts participated in the discussion: Dr Atef Shibl, Dr Stefan Weber and Dr Shafi Mohammed from Cleveland Clinic, Abu Dhabi, UAE. The discussion focused on the importance of developing and implementing effective stewardship programmes in hospitals and the community.

The teaching, learning and practice of pathology depends on good understanding of microscopic morphology. Demonstrating microscopic features and understanding those by conventional method is often frustrating. Practicing pathologists also need affordable hardware and software to capture, share, preserve and print histopathology images. Camera attachment, multi head microscope, digital microscope and virtual microscopy are available but these are expensive, take table space, and only few institutes/ pathologists with limited resources can afford to invest in these.  

Rise of digital cameras have generated a shift toward digital-image capturing methods, including mounted digital cameras and whole slide digital-slide scanning. Digital image capture techniques – whole slide imaging (WSI) have introduced new applications for slide sharing and second-opinion consultations of unusual or difficult cases in pathology. This has created a new branch: digital pathology. Digital pathology is an image-based information environment which is enabled by computer technology that allows for the management of information generated from a digital slide. Digital pathology is enabled in part by virtual microscopy, which is the practice of converting glass slides into digital slides that can be viewed, managed, and analysed on a computer monitor. With the advent of Whole-Slide Imaging, the field of digital pathology has exploded and is currently regarded as one of the most promising avenues of diagnostic medicine in order to achieve even better, faster and cheaper diagnosis, prognosis and prediction of cancer and other important diseases. Updates on digital pathology can be found on Digital Pathology Association website.

With their recent surge in popularity, smart phone cameras have become a widespread cost-effective method for pathology image acquisition. In addition, software/apps/technologies useful for image and video management are freely available from Google app store. Therefore, we thought of exploring the possibility of smartphones and its technologies as an affordable way to get introduced to basic functions/ applications of digital pathology.

Photomicrography by Smartphone

Manual method: While taking photomicrographs by smartphone camera, we need to hold the mobile with steady hands, a little away from the eyepiece, align, focus and click. This technique is described by Annie Morrison et al. This is quite tricky and to start with, requires practice, patience and time.

DIY (do it yourself) devices: A simple and easy solution to keep appropriate distance between eyepiece lens and mobile camera is the adaptor. Adaptor makes focusing easier and helps to steady hands. Though many have used paper roll as DIY device, a better option is PET/plastic bottle. We can simply cut the bottom of a suitable plastic bottle which fits the eyepiece and use it as an adaptor. However, adaptor is only half the solution- we still have to hold the mobile and cannot move slide or alter focus. With further innovation, we can make hands free display system easily. I have shared this innovation on PathoIndia website which was well appreciated and was published as power point article in May 2015.

Commercially available attachments: Few attachments are available for holding smartphones and attaching them to microscopes. These are mostly designed for specific models of microscopes or smartphones. Some models can be used even for telescopes or binoculars. Use of these attachments is discussed by Roy et al in their article in Journal of Pathology Informatics. Recently I have also developed and patented an attachment which can be used on any microscope for any smartphone or tablet.

Uses

Contemporary smartphones have many applications which are already built in: camera – to shoot microscopic images and videos, file manager for renaming images in files/ folders at specific location; Bluetooth for transfer of data without wire and internet. Images can be stored on Google cloud drop box. Screen cast/mirror can be used for viewing images on bigger screens with or without wire. Many free downloadable apps are available for image and video editing and sharing. Video calls can be used for live telepathology. We can record these sessions by screen recorder application. Panorama function can be used for covering larger areas of each section. All these functions can be used in teaching of histomorphology to students. Similarly, images and videos can be shared on social media for fast and easy discussion amongst pathologists.

Advantages of Smartphone Photomicrography Using Attachments:

1. Economy
2. Existing microscope remains in use
3. We can exploit potential of smartphones (which everyone already has)
4. No need to spend on software as free/economical apps are available from Google Play Store. We can choose which apps to use.
5. Automatic upgrade of camera as we upgrade our smartphone.
6. Our data is always in our pocket. Images/videos can also be stored on remote server/cloud.
7. We can take advantage of continuous improvements in smartphones, storage capacity, its technologies/apps and internet speeds to upgrade our system.

Quality of images: This depends on the smartphone camera and megapixels. Basic models of top brand devices have good quality camera; images with 5 megapixels camera are fine.  For other devices generally 8-megapixel images are satisfactory.13+ megapixel cameras will give excellent images. For viewing images, display resolution is important. Tablets are more comfortable for viewing images as they have larger screens. Quality of microscope optics improves with quality eyepiece (especially wide field eyepieces) and objective lenses that provide better images. In addition, LED light source gives sharper images without colour abrasion.

Limitations

In spite of the advantages of smartphone photomicrography in teaching and practice of pathology, its limitations in histopathology practice must be understood.  Limited number of images/subjective limited data submitted cannot be compared to whole slide images obtained by high end state-of-the-art slide scanners especially when seeking opinion on difficult cases.

Further Scope

This innovation has unlimited scope for further research and development. Engineers can develop robotic arm/stage which can be manipulated remotely. We can interact with information technology professionals to develop user friendly apps for teaching purposes, for practicing pathologists and for telepathology use in primary healthcare facilities. I should mention that a mobile application for rapid diagnostic surgical pathology consultation has been described by Hartman et al.

Summary

Smartphones and related technologies are quite useful as affordable and simple tools for practicing pathologists and pathology teachers (with limited resources) to a great extent. However, its limitations should be understood. It can serve as small step to get experience of digital pathology. This sub-branch of digital pathology has further scope for research and development.
References available on request.

This brief commentary is based upon a talk given at MEDLAB 2018 in Dubai, UAE, which I was honoured to attend as president of the College of American Pathologists. As the title indicates, although an experienced laboratorian can often sense when something isn’t quite right, quality improvement is more about diligence and intentional excellence than intuition. In a few days at MEDLAB and over the course of visits to CAP-accredited laboratories nearby, (including a day-long educational event at the American Hospital Dubai and a workshop sponsored by National Reference Laboratory), I saw that friendliness, diligence, and intentional excellence were in good supply in this new-to-me segment of the global community of pathologists and laboratorians. I am confident that the pace of progress in laboratory quality improvement will only continue to accelerate as international collaboration further diversifies the contributing experiences that drive innovation. 
And now, to our topic… 

A complex, evolving context

Reports from the clinical laboratory have always provided high-impact data points for diagnostic and therapeutic decision making. In recent years, the rapid emergence of targeted therapies has created accelerated demand for companion diagnostics. Clinical laboratories are becoming more visibly integrated in the healthcare system (department-to-department internally and facility-to-facility across the globe) than ever before. All of this makes the old-school notion that the laboratory is an island unto itself more archaic by the minute. It is becoming clearer to more people that excellence in laboratory testing is foundational to patient safety and healing. 

Within the healthcare facilities, a higher profile for clinical pathology has boosted awareness of the human cost when sensitive specimens are improperly managed, especially in the preanalytical phase. Laboratory professionals are educating their partners in specimen collection and transport about the ways that temperature, time, and packaging quality can impact the utility of biological specimens provided to us for analysis. More people are beginning to understand that human materials that are not carefully protected and promptly delivered to the laboratory can quickly degrade. The information that we can elicit from the specimens they collect and transport can define a patient’s future, as our patients are their patients, too. Laboratory quality is everyone’s job.
External quality assessment has one overriding goal: to enhance the quality of care. As the value and promise of laboratory medicine becomes better understood across domains, collaborative efforts to make healthcare quality more uniform and accessible across the globe are growing in tandem. In that context, external quality assessment is getting more attention, as are ways to standardise and harmonise clinical laboratory test results for analytes without available reference measures.

The Mechanics

External quality assessment programmes involve arms-length agreements with providers that validate the accuracy and precision of laboratory test results. The goal is to ensure consistent excellence in clinical laboratory testing so that results are equivalent across sites. 

Proficiency testing is the best-known tool of external quality assurance. Subscribing laboratories receive blinded analytes (sometimes called challenges). The specimens are batched with routine tests and treated exactly like actual patient samples, except that results are sent to the testing programme rather than an ordering physician. The testing programme compares findings to those of peer laboratories to assess consistency and congruity. Failure is defined by a specific significant variance from the mean value for each test within the peer group. 

When a proficiency testing analyte is found to have a concentration or activity equivalent to that of a native (“real”) clinical specimen, that analyte is said to be commutable. Due to the high demand and need for accessibility, proficiency testing analytes are manufactured in large quantities with the most economical materials that will yield results within a clinically relevant range. They are not commutable.

If the macro goal is to make every patient’s test results useful wherever and whenever they seek treatment, then the micro goal may be to help laboratory colleagues appreciate how all the pieces fit together and how they fit in. To that end, much of my discussion at MEDLAB focused on potential new uses for (or approaches to) external quality assessment, viewed through the lens of accuracy-based proficiency testing, a laboratory quality solution developed by the College of American Pathologists.

Accuracy-based Testing: Enter Commutability

The first accuracy-based proficiency testing materials were developed to address inaccurate creatinine results that were causing misclassification of the estimated glomerular filtration rate (eGFR) in patients being screened for chronic kidney disease. The College of American Pathologists introduced this challenge in its proficiency test menu in 2004, naming it the Accuracy-based Creatinine Calibration Verification/Linearity (LN24) Survey.

Accuracy-based challenges are matrix neutral – they contain no stabilisers or antimicrobials, and have limited stability as a result. Their manufacture requires donor/disease-based material, which is in short supply. Target values for accuracy-based challenges are set by high-level reference methods and participant results are graded against the targets rather than peer groups. The 700 surveys offered through the College of American Pathologists programme include seven accuracy-based challenges. Accuracy-based challenges are provided by other external assessment programmes as well.
Because accuracy-based materials contain no additives to prevent breakdown or microbial growth, they must be continually frozen to ensure stability. Laboratories ordering short-stability products need to work closely with their proficiency testing providers to ensure that specimen integrity is continually protected. Distance to the destination as well as time for customs inspections and other importation requirements must be taken into account. 

Commutability is the gold standard. In a perfect world, physicians treating a patient from the United Kingdom who became ill while travelling in China, the United Arab Emirates, or the United States, could comfortably rely upon laboratory test results recorded in his or her home medical record. That’s the big picture. Not the picture as it stands now, but one coming into focus through the collaborative work of laboratory professionals across the globe. Several organisations (eg, the Clinical Laboratory Standards Institute, International Standards Organization, and European Union) are pursuing commutable reference materials for proficiency testing programmes and other quality control purposes.

Definitions from the Clinical Laboratory Lexicon

• Test results from different methods and manufacturers that agree (within clinically acceptable limits) are said to be harmonised.
• When a proficiency testing analyte is found to have a concentration or activity equivalent to that of a native (“real”) clinical specimen, that analyte is said to be commutable. This means that test results between field methods and reference methods can be compared directly.
• Routine proficiency testing materials are artificially produced and not commutable.
• When two clinically equivalent and properly prepared analytes yield different results, the cause is most likely to be calibration bias (what is true), random bias (what is imprecise), or matrix effects in the sample. While any laboratory test is vulnerable to error or bias, only artificially produced proficiency testing materials have matrix effects.
• Matrix effects are common, widespread artifacts of material processing (ie, stabilisers and other add-ins to protect against the effects of temperature shifts during shipping). The magnitude of a matrix effect is unpredictable and will vary by method and instrument. At present, only accuracy-based challenges are without matrix effects.

The 17th edition of the MEDLAB Middle East Exhibition and Congress, the world’s largest medical laboratory event, has successfully celebrated its second consecutive year as a standalone event at the Dubai International Convention & Exhibition Centre in the United Arab Emirates (UAE). Previously running as part of the Arab Health Exhibition & Congress, the four-day MEDLAB Middle East forum, which welcomed over 700 exhibitors and more than 25,000 attendees from over 130 countries, took place from 5-8 February 2018 and was officially inaugurated by His Excellency Humaid Mohammed Obaid Al Qatami, Chairman of the Board and Director General of the Dubai Health Authority.

Speaking at the opening, H.E. Humaid Al Qatami said, "MEDLAB Middle East is an important opportunity to learn about the best equipment and modern technologies in the field of medical laboratories, which is a major part of the healthcare system. The exhibition is also a scientific platform for the exchange of the successful international experiences and developments related to research and laboratory studies. The Dubai Health Authority pays attention to this, and expresses its interest to all developments aimed at upgrading services - diagnostic and therapeutic.”

According to a market report by Mordor Intelligence, the global In-Vitro Diagnostics (IVD) market was estimated at USD 74.69 billion in 2016 and is forecast to reach USD 96.93 billion by 2021, growing at a CAGR of 5.35% during the forecast period. While the US (contributing to around 31% of the global IVD market) and Europe currently dominate the market owing to their increasing healthcare expenditure and improved clinical laboratory infrastructure, they estimate that there could be a rise in the IVD market share from the emerging economies as well, as diagnostic companies are focusing on capitalising on the untapped markets in the medical sector.

The Industry Convenes

This year, the MEDLAB Middle East exhibition focused on innovations in laboratory solutions and on the exploration of new business opportunities in the global medical laboratory and IVD fields. Visitors had the opportunity to source products and services from over 700 national and international companies featuring the latest innovations from over 40 countries and 12 country pavilions including France, Germany, the UK, the US, Egypt and China. The popular Dealers & Distributors Wall & Lounge enabled attendees to source the latest products from more than 200 medical laboratory product categories.

MEDLAB Middle East also provided leading global and regional healthcare companies such as Abbott, Siemens Healthineers, Snibe Diagnostics, and Beckman Coulter, with a platform to engage with their clients and partners, particularly those from the Middle East.

As the medical laboratory industry continues to evolve, one of the big trends today is precision medicine. Siemens Healthineers, titanium sponsors of MEDLAB Middle East were on the exhibition floor to connect with customers and discuss how they are using innovation and acquisition to address the needs of the market.

“MEDLAB is by far the biggest show in the region and it is also one of the top shows for laboratory diagnostics in the world. So, for Siemens Healthineers, it is very important to be present here to meet our customers and business partners in one great location,” said Romain Fournials, Vice-President – Laboratory Diagnostics, Siemens Healthineers. “This year it is all about the new Atellica family, particularly the Atellica COAG 360 system – a fully automated high-volume coagulation system that unifies five testing methodologies.”

Meanwhile, Al Hayat Pharmaceuticals were showcasing their latest product lines in the market. “We are pleased to be back at MEDLAB Middle East as we were one of the first companies to exhibit at the show when it first launched,” said Anwar A. Abu Eida, who is the sales manager for Al Hayat Pharmaceuticals. “The show has now become more than just a regional show and we are proud to be part of the global MEDLAB series. It is a great opportunity for our principals to meet face-to-face with our customers from all corners of the globe.”

According to Koji Dohi, who is the marketing manager for IVD products at Fujifilm Corporation: “MEDLAB is a great platform for us to communicate with potential customers from across the MENA region and we are here to introduce our 9th generation dry chemistry analyser – the DRI-CHEM NX700, our high-end specification machine to our regional audience.”

Also, as Dhiren Wangle, Director, Erba Mannheim, explained: “We see a lot of our customers from as far as Asia converging at MEDLAB in Dubai. It is great event for us to launch new products into the market as well as an opportunity for us to discover what is happening in the industry. We are here to talk about the launch of three new products to the market - our new fully automated urine chemistry analyser, a new coagulation analyser and a five-part haematology analyser. We are really excited to see the response from the market.”

Problem Solving Through Collaboration

The educational agenda at MEDLAB Middle East was once again extremely well received by more than 6,500 delegates who were able to participate in raising the standard of practice in medical laboratories and in the development of better service for patients across the region. Featuring 17 CME-accredited conference tracks, including five new clinical tracks designed to enhance collaboration between laboratory professionals and clinicians, the MEDLAB Congress was the ideal platform to discover innovations in medical laboratory testing.

“The introduction of clinical tracks alongside the laboratory-focused conferences will aid in accurate interpretation, quick reporting and diagnosis, therefore strengthening the laboratory’s ability to provide clinical decisions and improve the overall quality of service and care in the region,” said Tom Coleman, Group Exhibition Director, MEDLAB Series. “The tracks that we focused on for 2018 were oncology, obs-gyne, endocrinology, cardiology, as well as antibiotic use and misuse.”

At the congress, leading medical practitioners discussed the increasingly important role that clinical laboratory professionals play in today’s healthcare system, from early detection and diagnosis to customised treatment plans based on the patient’s unique genetic structure.

The Laboratory Management conference centred around understanding the collaboration of administrative and medical leadership and the dynamics of quality management and safety improvement in a medical laboratory of any size, scope, or speciality. Meanwhile, the Histopathology conference provided a comprehensive review of the latest histopathological, cytological and related technical advances, and featured a discussion to exchange views regarding the latest research on cell biology using molecular tools and genomic data. Other laboratory conference tracks at MEDLAB Middle East included Molecular Diagnostics, diabetes testing and management, haematology, laboratory informatics, Point of Care Testing, tumour markers, clinical chemistry, blood transfusion medicine and cardiac markers.

A much-awaited educational forum at MEDLAB was the Heads of Labs Masterclass, which took the approach of problem solving through collaboration. As Coleman explained: “This masterclass offered an immensely valuable discussion on clinical laboratory management challenges and questions that arise in the everyday operation of the clinical lab. Focusing on practical solutions to the most common, but not necessarily easy-to-solve, problems encountered both in public and private laboratories, this forum was successful at strengthening collaboration and cooperation amongst regional leaders in the lab to improve patient services.”

Spotlight on Women’s Heath

Previously running as a standalone event, the 10th edition of the Obs-Gyne Exhibition & Congress was co-located with MEDLAB Middle East for the first time to further educate women's health physicians of the importance of routine laboratory investigations frequently ordered, and to enhance the unity amongst obstetricians, gynecologists and laboratorians in the region.

The show provided a platform for over 2,500 women’s health specialists to gather alongside more than 60 of the industry's leading manufacturers, and exchange knowledge, share best practice and, ultimately, improve the level of patient care provided. Featuring four plenary tracks – General Obs-Gyne, Gyne-Oncology, Maternal and Fetal Medicine, and Infertility – the congress introduced an international perspective and relevant regional expertise on women’s health issues prevalent worldwide.

MEDLAB Goes Global

Since its launch in Dubai in 2002, MEDLAB has established itself as one of the largest laboratory events in the world. The MEDLAB Series, now with a portfolio of seven annual trade shows across the Middle East, Asia, Europe, the Americas and Africa, bolsters the impact of laboratory medicine on patient outcomes by focusing on bridging the gap between lab professionals and doctors.

“With 15 years of growth and development, MEDLAB is a proven exhibition model on an international scale,” said Coleman. “MEDLAB continues to give visitors from across the world an opportunity to access cutting-edge laboratory products, next-generation technology, innovative services and world-class educational content.”

Now in its fifth year, the MEDLAB Asia Pacific Exhibition & Congress will be returning to Suntec Singapore Convention & Exhibition Centre in Singapore on 2–4 April 2018. MEDLAB Asia Pacific will provide a platform for leading companies to showcase current technologies and clever innovations in the field of laboratory and diagnostics.

Meanwhile, the second edition of MEDLAB North Africa - the region’s only dedicated laboratory exhibition – will take place alongside the Mediconex Exhibition & Congress from 14-16 April 2018 at the Cairo International Convention Center in Cairo, Egypt.

In the US, thousands of medical laboratory industry experts and equipment suppliers from across Northern and Latin America will be converging on the Orange County Convention Center in Orlando, Florida, USA, from 17-19 July 2018 for the second annual MEDLAB Americas Exhibition & Congress. MEDLAB Americas exists as part of the 28th edition of The Florida International Medical Expo (FIME) and provides first-class networking opportunities for laboratory experts, scientists, researchers and clinicians as well as featuring cutting-edge lab products and services from leading international medical equipment and device companies. 

A recent addition to the MEDLAB Series portfolio is the European edition in Barcelona, Spain. With the European In-Vitro Diagnostics (IVD) market expected to reach USD 15.5 billion by 2024, a platform such as MEDLAB presents a huge opportunity for global laboratory industry leaders, including manufacturers, dealers and distributors, to make inroads into the European market. Taking place at the Fira Barcelona-Gran Via in Barcelona from 24 October 2018, more than 3,000 industry professionals and +120 exhibiting companies are expected to attend the 2nd edition of Europe’s leading event for laboratory management and diagnosis.

According to Coleman: “The launch of MEDLAB Europe was in line with our global expansion strategy for our MEDLAB series of events. MEDLAB Europe will generate substantial value for our customers and partners by driving further product innovation and deeper engagement in these specific markets.”

Elsewhere in Africa, the MEDLAB Series has a strong presence with two annual shows. MEDLAB East Africa will take place from 25-27 September 2018 at the Visa Oshwal Centre Westlands in Nairobi, Kenya while MEDLAB West Africa is set to welcome thousands of medical laboratory professionals to the Eko Hotel in Lagos, Nigeria from 10-12 October 2018.

MEDLAB All Year Round!

Omnia360.com, Informa’s global medical directory, formed an important part of MEDLAB Middle East 2018 as attendees are now able to stay connected with exhibitors and browse products and services before, during and after the show. Year-round access to the portal enables visitors to source information on companies exhibiting at Informa Life Sciences’ shows as well as interact with and explore products beyond the show floor, whenever and wherever it is needed.

“We have an average of 1,000 products currently going live on the website every week. With over 4 million page views and more than 200,000 users, Omnia’s ability to transform an annual event into a 365-day exhibition experience has been validated beyond doubt,” said Joseph Chackola, Publications Director, Informa Life Sciences, Dubai, UAE.

Sarstedt AG & Co., with headquarters in Nümbrecht, Oberberg District, Germany, is one of the world‘s leading providers of laboratory and medical equipment, and develops, manufactures and sells equipment and consumables in the field of medicine and science.

Founded in 1961, the company has continued to grow to the point where it now employs a workforce of 2,600, with 1,100 employees working in the Oberberg District alone. The Sarstedt Group comprises 33 sales organisations and 13 production sites in Europe, North America and Australia.

Customers can rely on the highest level of quality, availability and product support. “Sarstedt always develops solutions characterised by ease of use, safety and the latest technology,” highlights the   Sarstedt family, who own the Group. Sarstedt offers extensive services under one roof, from the initial idea through to sales and distribution. Most products are developed in the company-owned R&D centre to actively advance innovations – from the initial idea through to the finished product. Approximately 90 per cent of the entire product range are manufactured at Sarstedt production sites and are sold around the world predominantly through the company’s own sales organisations.

Sarstedt products are used directly on patients, in a wide variety of laboratories, university research, clinical chemistry, biotechnology and food processing, clinics and transfusion centres. Therefore, they must conform to the highest safety, precision and hygiene standards. As a global company, Sarstedt ensures that the products meet the statutory and official regulations of various countries and markets. Since its foundation, the company has placed great value on research and development. A high  demand for quality, continuous R&D, committed and very well trained employees as well as  automated  processes are the components which  make up the excellent quality “Made in Germany“.

The diagnosis of haemoglobinopathies has become an increasing challenge in multinational European countries, Australia, USA, Canada and recently in emerging haemoglobinopathy ‘hot-spots’ such as the Gulf Countries.  The United Arab Emirates (UAE) and Dubai, in particular, is one of those countries where haemoglobinopathies pose a national health concern. Accordingly, over 200 nationalities were potential candidates for a mandatory national screening programme launched in 2006.

Haemoglobinopathies (a-thal, b-thal, Hb variants) occur at a relatively high frequency in the UAE. Detection of common haemoglobinopathies is simple; however, the complexity arises from extensive a- and b- globin gene interactions. The ensuing genotypes and phenotypes result in widespread heterogeneity thus rendering Dubai the most heterogenous nation worldwide hitherto with 55 b-globin gene defects.

The key objectives for the Population Screening Programme in Haemoglobinopathies in the UAE:

• To improve level of awareness about the six most common genetic disorders
• Share information on credible, available, affordable and accessible preventive tools
• To find cost effectiveness of population screening programme i.e. cost of management of vs prevention of genetic blood disorders

Case Study: ‘Emirates Free of Newly Born Thalassemic Children'

The above campaign was launched to raise awareness on genetic blood disorders such as Thalassemia, Sickle Cell anaemia and G6PDH (Glucose-6-phosphate dehydrogenase) and tackle public health concerns and related issues for creating a healthy community.

Situation at the time of launch: Thalassemia was a major public health issue in the UAE. The official data available showed the prevalence of Thalassemia to be 12% among the target population.

Structure of the programme: Developed by the scientific committee after an in-depth study of the existing prevalence and challenges, the structure was designed to meet the standards prescribed by WHO for population screening programme which are:

• The target disorder should be a substantial health problem

• The disorder should be diagnosable in a latent or pre-symptomatic phase
• The natural course of disorder should be understood
• A simple, safe and sufficiently precise screening test should exist to detect the target disorder
• An adequate infrastructure for screening, diagnostics, and treatment should exist and the costs of a screening programme (including test, diagnosis and treatment) should be in proper relation to total costs of the disease
• Screening for a disorder should be a continuous process (incidence screening) instead of a singular event (prevalence screening)

Methodology: The campaign team of 260 volunteer ambassadors from 13 UAE educational institutions including Higher Colleges of Technology, UAE University and Dubai Women’s College were guided by the UAE GDA research team.

Impact of Population Screening Programme between 2007 to 2016:

• The post campaign surveys showed that the awareness of genetic screening increased among student communities relatively from 6 percent to 96 percent.
• A total of 11281 UAE national female college students were screened during 2007-2011. The a-thal / iron def. anemia, b-thal, bS and G6PDH carrier frequencies were 54%, 4.2%, 1.8% and 1.9%, respectively. The relatively lower incidence of bS was attributed to a regional effect where the samples were from the northern emirates.

Cases detected and the comparison of cost of management vs prevention:

• The screening test costs 120 dirhams ($33) in UAE GDA lab.
• Price of caring for a child with thalassemia, estimated at 1.2 million dirhams ($327,000) up to the age of 16.

Conclusion: In the UAE, successful screening programmes have played a profound effect in reducing the birth of thalassemic babies and had an enormous impact on public awareness of haemoglobinopathies.

The UAE Genetic Diseases Association was founded in 2004 as a nonprofit organisation and strives to reduce the prevalence and impact of common genetic disorders in the UAE through preventative awareness programmes, screening based on research studies and knowledge sharing, conducted by experts in the field using the most innovative technology at the lowest costs. UAE GDA conducts research in the fields of Autism, Alzheimer’s, Breast Cancer, Celiac Disease/Gluten Intolerance, Childhood Cancer, Duchenne Muscular Dystrophy, Diabetes type 2, Familial Hypercholestremia, G6PD, Neural tube defects, Sickle Cell Anaemia, Thalassemia and Vitamin D deficiency.

With 4,000 procedures per year including 3,000 ablations and 1,000 device implantations, the number of interventions by Prof Carlo Pappone’s team at the Policlinico San Donato Research Hospital and San Rocco Clinical Institute (San Donato Hospital Group) is the largest in the world for an electrophysiology laboratory. But it is not just the number of cases treated that makes the Department of Clinical Arrhythmology and Electrophysiology of Policlinico San Donato (San Donato Milanese, Milan) one of the leading centres on an international level. The quality of the procedures and the predisposition for innovation attracts patients from all over Italy and overseas, and doctors from all corners of the world visit the hospital to learn how to use the state-of-the-art techniques devised by Prof Pappone.

A pioneer in the field, Prof Carlo Pappone created what is known as the “Pappone approach”, a method that describes how to identify and eliminate atrial fibrillation circuits and establishes the criteria for validating its efficacy. Today, circumferential ablation of the pulmonary veins, described by the “Pappone approach”, is the most widely applied technique in the world for the treatment of persistent and chronic atrial fibrillation.

Atrial fibrillation is an acquired form of arrhythmia, a disease that strikes an increasingly large proportion of the population aged over 50 years, due to ageing of the heart and, in particular, its electrical system. “Arrhythmia upsets a magical balance in our lives. Every day our heart beats some hundred thousand times, and the magic lies in the fact that we are not aware of it. On the contrary, if we have arrhythmia we are well aware of it as it beats too quickly or slowly. This sense of malaise, called palpitation, may have different causes. We should worry about it if the heartbeat is too fast while we are resting or if it is too slow while we are exercising,” explains Prof Pappone.

“Atrial fibrillation, together with ventricular tachycardia, is a form of arrhythmia that can be acquired during the course of our lifetime, together with the typical aging of the heart. As the hearts gets older the electrical system may conduct the impulses more quickly or slowly. These are the two types of arrhythmia with the highest incidence rate in the world population, following the ageing of the population and the prolongation of life,” he says.

 There are also other types of arrhythmia, present from birth or of genetic origin. “We are talking about paroxysmal tachycardia, abnormalities that develop in the embryo, causing irregularities in the conduction of the heart’s electrical system. These individuals may suffer accelerations in their heartbeat up to 200-250 beats per minute, but these forms of arrhythmia are benign and have no clinical consequences. The genetic forms are much more serious: it is written in their DNA that they could suffer arrhythmia episodes at a certain point of their lives, predisposing them to the onset of complex ventricular arrhythmia and even a risk of sudden death,” elaborates Prof Pappone.

The various forms of arrhythmia are not all treated in the same way, but with specific techniques according to the mechanism that causes them. “Radiofrequency ablation is the most widely adopted technique in the world and, in most cases, actually cures the disease. It is applied both to congenital arrhythmia and to ventricular tachycardia, atrial fibrillation and atrial tachycardia. Through special mapping systems, the arrhythmic circuits – that is, the points where the electric pulses are conducted more or less rapidly - are located and defined and the normal electrical stability of the system is restored using radiofrequency waves,” explains Prof Pappone.

Excellent results have also been obtained in patients suffering from Wolff-Parkinson-White syndrome, where Prof Pappone, together with his team, is the historical pioneer in its treatment by ablation. Through observation of the patients in the electrophysiological study and the elimination of the short-circuits responsible for the arrhythmia, which is often asymptomatic, the recovery rate has reached levels of about 95-99%. There are, however, forms of arrhythmia that cannot be eliminated but have to be managed by implanting a device. “This is the case of patients suffering from ventricular fibrillation, in whom we implant a defibrillator, a small device that detects arrhythmia and automatically eliminates it, thus preventing a heart attack. On the contrary, for atrioventricular blocks, the only possibility is to implant a pacemaker to restore normal cardiac conduction,” he explains.

The progress made in arrhythmology has led to a cure being found for the most widespread forms of arrhythmia and now gives hope even to patients suffering from rarer diseases, that are not easily diagnosable and often, a cause of sudden death. The scientific studies in progress at Policlinico San Donato trace out the challenges for the future. “We have discovered that many genetically encoded forms of arrhythmia are expressed at certain points of the cardiac muscle, and that they can be identified using advanced mapping systems. These electric abnormalities do not give any signs of their existence for most of the patient’s life and only manifest themselves once. Therefore, they cannot be prevented or treated because many of the patients affected are not aware of them. This is why, today, all over the world, around three million people die of a sudden heart attack; 60,000 in Italy alone. We are convinced that we can identify these patients before the disease is manifested because we have discovered how to diagnose the condition. We believe this to be an epoch-making discovery: we could offer a cure to many young people otherwise destined to die early and suddenly,” reveals Prof Pappone.

Widely regarded as the pioneer in the field of treatment for Brugada Syndrome, he says, “Our group has opened up a Pandora’s box on potentially lethal forms of arrhythmia, which strike the population aged between 15 and 35 years. It was discovered for the first time at Policlinico San Donato that these genetic diseases – until now considered simple electrical disorders – are fully-fledged diseases in which an anomalous gene encodes a substrate situated at a specific point of the heart, in its outer part, that is the epicardial region of the left or right ventricle. For the first time in the world and in the history of medicine, a technique has been devised to identify these substrates and eliminate them with radiofrequency waves, thus curing a patient suffering from this genetic disease. Until two years ago, this was considered an impossible objective for science. Now, at Policlinico San Donato, in about three years, over 250 patients suffering from Brugada Syndrome have been cured. Numerous doctors coming chiefly from Asia – a continent on which this disease is widespread –now visit our laboratories to learn the technique.”

The next objective seems to be closer to science fiction than reality: to penetrate into the “magic” of the heartbeat to predict and prolong a person’s life span. “We believe that, as time passes, areas with impaired functions of the cardiac muscle can develop due to electrical abnormalities and that these regions can become larger over the years, thus causing our heartbeat to slow down progressively or stop suddenly,” he elaborates. “By studying the genetic expression of the electrical activity of the epicardium, we can map the outer part of the heart, identify the damaged regions and, through the application of extremely superficial electromagnetic waves, teach the cells how to communicate with one another correctly, so as to prolong their lives. It is a target that we have set ourselves over the next three years.”

It appears evident that the integration between specialised medical skills and the use of advanced technology is the winning combination for obtaining new clinical and scientific results. “The arrhythmologist of the future will certainly be a heart specialist with in-depth knowledge of cardiology. Unlike all other organs, the heart is the only organ that functions with an electrical current and, to think about it, the only one that moves autonomously inside the body. An electrical machine must be understood and treated by an electrician, and this is why the figure of the arrhythmologist is crucial for the treatment of diseases that have this origin,” he explains.

It is the ideas that stem from the experiences of arrhythmologists that are providing the input for multinational companies to develop increasingly advanced, precise and personalised technologies and instruments. From the mapping systems for studying the heart to the instruments used for the treatments (catheters, devices and software), most of the technologies currently used in electrophysiology laboratories all over the world are said to have originated from collaborations between Prof Pappone’s Arrhythmology and Electrophysiology laboratories and the leading companies. “Today, we are talking above all about technologies aimed at determining the mechanisms that lie at the basis of cardiac arrhythmia, a change in policy with respect to the traditional orientation towards interventionism. Knowledge of the mechanisms that cause diseases lie at the basis of progress in every field and will enable us, in the near future, to obtain more effective treatments, applicable in the short term, which can reach all the patients in the world,” he says.

In fact, the high costs of electrophysiology determine an inhomogeneous distribution of the treatments. “For arrhythmia, there is no scientific democracy; rather, it is a monopoly of the richer countries,” opines Prof Pappone. “In some developing countries, the discipline does not exist and many children die of forms of arrhythmia that would have been extremely easy to cure in Europe. Policlinico San Donato has a robotic system capable of performing operations at a remote location: today, an operation could be performed on a child in Africa simply from a desk in our lab using a mouse. The child, in a lorry fitted out and set up as a laboratory, could receive the electrical impulses transmitted directly from our hospital. I sincerely hope that this project will be implemented over the next few years because I firmly believe that everyone, wherever they are born, should have the same opportunities in terms of longevity and quality of life.”

Imagine a world where drugs are designed to fit an individual’s genetic profile and can fight a particular variation of a disease? That exciting medical development is well within our grasp with Pharmacogenetics. It is already making significant inroads in the United States and many industry experts hope that one day it can be rolled out universally to benefit everyone.
Pharmacogenetics is based on the principle that an individual’s response to certain drugs is determined by their genes. It is then possible to minimise the side effects by matching the right drug and dose to the right patient. This can also maximise the drug’s effectiveness.

By analysing an individual’s DNA through blood from a finger prick or cells from a mouth swab, doctors can then come up with a drug sensitivity profile for that patient. This can avoid exposing individuals to doses of drugs that could be ineffective or harmful to them. The other benefits could be reducing costs and cutting the length of hospital stays.

Side-effects affect
According to research from Harvard University, adverse drug reactions rank 4th as the leading cause of death in the United States (US). One of the causes is the large degree of variability in how the body metabolises the drug. In other words, a drug that suits one person could be too much or too little for another.

According to analyses from Vanderbilt University School of Medicine in Nashville, around 50% of hospital patients receive a drug in any one-year period that could cause serious side effects because of that person’s genetic makeup. A study which examined only six drugs, estimated that drug-gene tests could eliminate about 400 adverse events in a patient population of 52,942. Significantly, the number of avoided ailments would climb dramatically, probably into the hundreds of thousands, if tests were performed on more than six drugs across the US population.

Tracing the DNA road map
Pharmacogenetic testing is a relative straightforward process. After a swab is taken from inside the cheek the sample is sent to a laboratory for DNA profiling. Keith Reilly of TLK medical, one of the companies that makes the tests told the Express newspaper in the UK that it measures 14 genes and biomarkers that metabolise through the liver and covers 90% of prescription drugs on the market.
He said: “It is primarily used to show how patients metabolise prescription drugs. It can be used to measure adverse reactions and show whether patients should be taking more or less of a particular drug.”

A colour-coded report is then sent to the patient which alerts medical professionals to any medications they might be adverse to but also advises the optimum dose of medications they might already be taking to get the maximum benefit from that drug.

The test currently costs around $1,700 but many healthcare professionals feel it is money well spent if it brings tangible improvements to a patient’s health and well-being. Not to mention the savings it can make for state-funded health provision.

Hurdles to overcome
However, there are obstacles to the tests’ widespread use including the lack of insurance reimbursement and confusion over when and how to alter drug prescriptions. In an article in the Scientific Amercian, Dina Fine Maron reported that the insurance companies will cover only some tests because not all have been definitively shown to improve clinical outcomes. Clare Krusing, a spokesperson for America’s Health Insurance Plans, the national trade association for the health insurance industry said in the article that coverage varies for these tests as a result of limited clinical evidence around their effectiveness for patients.

There are signs that this hard line is beginning to soften, said Maron. “Vanderbilt officials say that in the past few years reimbursement policies from some insurers have evolved, and companies have started to cover a small percentage of the costs. Other hospitals are taking note.” The University of Maryland Medical Center has also started offering the test but primarily to cardiovascular patients. To cover the costs of the tests it has used clinical research grants from the federal government. But Maryland hopes to change over to billing insurance companies soon, according to the article.
Overall though fewer than 10 hospitals in the US are offering pharmacogenomics tests to certain patients. Maron claims that the other main obstacle to wider use, besides reimbursement, is the lack of a prescribing road map. “Many doctors were educated in an era before such testing was available so they do not even think to order them. And a lot of physicians would likely find they are not equipped to understand the results.”

Dan Roden, the assistant vice chancellor for personalised medicine at Vanderbilt University Medical Center believes that decision-support systems need to be installed. A busy doctor needs to be told the patient had genetic testing for certain variants, what the tests found and be given easy-to-understand guidance on what prescribing changes could be made, he remarked.
The accuracy of these tests is another important issue. The US Food and Drug Administration has recently taken steps to regulate genetic tests when they are offered directly to consumers. Wylie Burke, the chair of bioethics and humanities at the University of Washington has conducted extensive research on the social, ethical and policy implications of pharmacogenomics. She said: “Clinicians have an obligation to be competent and use technology in the patient’s best interest. In the case of genomics we have to be clear about what we don’t know. At the moment, there are only narrow ways in which we can truly say: yes, we know how to use this for benefit.”

DNA confidential
There are privacy issues that arise from giving over large amounts of information regarding a person’s DNA. Candi Cigar, research legal counsel from the Centre for Addiction and Mental Health, Ontario, Canada, said: “Privacy is a hot issue in research these days because of the large amounts of information given by a patient with the expectation of it being confidential. There is however the potential for it to be put out there and misused by people who were not supposed to have the information.

“There needs to be legislation in place to lay out what a person can or cannot do with someone else’s information. If you have information that is potentially identifiable you have to take certain steps to protect it. In pharmacogenetics, as the taking of samples and stripping it down to its DNA can be identifiable, it is important that it should only be used if consent is given. However, if this is breached and information gets out to third parties such as an insurance company who finds out that you are pre-disposed to certain diseases, they could refuse to enter into an insurance contract with an individual.”

In the USA, the Genetic Information Non-discrimination Act or ‘GINA’ legislation has been implemented which protects patients from other people such as insurance companies and employers investigating them in terms of their health status.

In terms of the liability for hospitals, research institutions and clinicians, Cogar said: “If the negligence lies in the information that was given by the researcher to the patient, there may be potential liability there. If the negligence lay with the clinician or the primary care-giver by changing the prescription without using good clinical judgment, there could be potential for liability there as well.”
In respect of the ownership of the DNA this is less clear but a few instances have occurred in the US which have tipped the balance towards the institution owning anything that has been taken out of the body.

The future is bright
If all these challenges can be overcome, pharmacogenetics could transform the treatment of patients worldwide. Just as our genes determine our hair and eye colour, they also play a crucial role in how our bodies respond to medications. At the moment, many drugs are of a ‘one size fits all’ variety but they simply don't work in the same way for everyone. It must be incumbent on scientists to determine who will benefit from a medication, who will not respond at all, and who will experience negative side effects which are a significant cause of hospitalisations and deaths around the world.

Personalised medications, more accurate methods of determining appropriate drug dosages, reduced polypharmacy, and an overall reduction in the cost of healthcare are some of the real and significant benefits of pharmacogenetics. What is more, it can reduce the cost of health care due to the reduction in the number of adverse drug reactions and the length of time patients are on medication.

The recently-opened iGenomeDx laboratory in San Antonio, US, boasts that patients will have a safer, faster, and more convenient pharmaceutical experience. “This specific type of lab testing is in great demand in the US. The targeted market and growth is exponential.”

The kidney marker uromodulin is experiencing a renaissance. Although first identified over 60 years ago, the protein languished until recently, when new research propelled it back into the spotlight. Uromodulin is directly linked to kidney function and its measurement can identify chronic kidney disease (CKD), even at the early stages. It is, moreover, a promising predictive marker for CKD, renal transplant outcome and cardiovascular disease.

Chronic kidney disease

About 600 million people worldwide have CKD, corresponding to about 1 in 10 of the population. Major risk factors for developing CKD include diabetes mellitus, hypertension, cardiovascular disease, obesity and increased age. Early CKD has no signs or symptoms and is considered a silent killer. Undetected CKD leads to progressive damage to the kidneys and loss of renal function.

CKD is divided into five stages, progressing from normal renal function despite kidney damage (stage 1), through mild (stage 2), moderate (stage 3) and severe (stage 4) impairment to renal failure (stage 5) requiring dialysis and/or transplantation. If CKD is detected early and managed appropriately, the deterioration in renal function can be slowed or even stopped. Treatment also helps to reduce the risk of associated complications such as cardiovascular disease. Thus, early detection of CKD is of huge benefit both in terms of patient outcome and healthcare cost savings.

Renal function is expressed as the glomerular filtration rate (GFR), which decreases as the disease progresses. Determination of GFR using exogenous and endogenous filtration markers is reliable, but is laborious, time-consuming and costly, and is therefore only indicated in risk patients. Determination of creatinine clearance, moreover, requires the collection of 24-hour urine. A simpler but less reliable method is estimation of the GFR (eGFR) by measuring the endogenous filtration markers creatinine and cystatin C in serum. These proteins increase due to retention as renal function diminishes. However, creatinine and cystatin C are not exclusively produced in the kidneys, but in all muscle cells or all cell nuclei, respectively. Therefore, factors such as body weight, nutrition or muscle mass have to be taken into account in the measurement, requiring complicated additional calculations. Exceptional circumstances such as extreme body size, non-conventional dietary intake (e.g. vegetarian diet, high-protein diet), skeletal muscle disease, paraplegia and amputated limbs can limit the reliability of the eGFR. Critically, creatinine does not provide a sufficiently sensitive response to early-stage kidney damage. The GFR can be reduced by as much as 50% while the serum creatinine value remains in the normal range. This so-called creatinine-blind area hinders the diagnosis of CKD in its early stages. Hence, new markers for early diagnosis of renal dysfunction are urgently needed.

Kidney-specific glycoprotein

Uromodulin is a glycoprotein which is synthesised exclusively in the kidneys, namely in the epithelial cells lining the thick ascending limb of the loop of Henlé (Figure 1). This region of the kidney is particularly sensitive to damage by lack of oxygen, inflammation, chemicals or pharmaceutical drugs. Uromodulin is secreted into both the tubular lumen and the blood. It is by far the most abundant protein in normal urine, while in serum the concentration is about a thousand times lower. The function of uromodulin is not completely understood. In urine, it plays a role in prevention of urinary tract infections and kidney stones, regulation of transport processes and activation of innate immunity. Its role in serum remains unsolved.

Interest in uromodulin was reawakened when genetic studies showed that a faulty uromodulin gene is strongly linked to CKD. Uromodulin is now at the centre of a frenzy of research to elucidate its function and its potential as a diagnostic marker. A multitude of studies have demonstrated its usefulness for diagnosing early-stage CKD, predicting outcomes of CKD and renal transplantation, and monitoring kidney vitality in other conditions.

Sensitive marker for early CKD

When renal function is impaired, the uromodulin concentration in serum or plasma decreases (Figure 2). Thus, uromodulin shows inverse kinetics to conventional markers like creatinine and cystatin C, which increase with declining kidney function. The uromodulin concentration exhibits a direct correlation to the eGFR. Moreover, in contrast to established markers, uromodulin concentrations change already in the early stages of kidney disease. Studies have shown that uromodulin measurement can distinguish between stage 1 CKD patients and healthy controls. Thus, uromodulin determination enables detection of renal insufficiency in the creatinine-blind area in the initial stages of kidney disease.

It is crucial not just to identify patients with CKD early on, but also to recognise those most likely to progress rapidly, in order to try to slow down the process or prepare the patient for renal replacement therapy. Patients with lower serum uromodulin have a generally poorer outcome and are more likely to progress to end-stage renal disease. Thus, uromodulin is also a helpful prognostic marker for CKD. Uromodulin is, moreover, a predictor of overall mortality in CKD patients. Individuals with low serum uromodulin have a significantly higher risk of dying from cardiovascular diseases and also other causes, possibly due to its anti-inflammatory potential.

Predictive marker in kidney transplant patients

In transplant patients, serum uromodulin can serve as a predictive marker. If the uromodulin level does not reach a certain value within a few days after renal transplantation, there is generally early failure of the graft. Uromodulin may also distinguish immediate graft function (IGF) from delayed graft function (DGF). This was demonstrated retrospectively in transplant patients with different outcomes (Figure 3). All patients had undetectable uromodulin prior to transplantation due to end-stage renal disease. Both IGF and DGF patients exhibited an initial rise in uromodulin up to day five following transplantation. In IGF patients the concentration continued to rise, reaching a stable level. In DGF patients, who subsequently required additional haemodialysis treatment, the uromodulin levelled off at a lower value. Thus, uromodulin may be a sensitive indicator of kidney graft dysfunction.

Risk factor for cardiovascular diseases

Low concentrations of serum uromodulin are also associated with a clearly increased risk of heart and vascular diseases. This was demonstrated in a recent study using blood samples from over 3000 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, who were referred for coronary angiography. The participants were monitored over a period of 10 years on average. Patients with low uromodulin showed a higher rate of accompanying diseases such as diabetes mellitus, high blood pressure and coronary failure. Furthermore, overall mortality was about twofold higher in patients with very low uromodulin. This association was independent of other cardiovascular risk factors, including eGFR. Adding serum uromodulin to established cardiovascular risk prediction scores improved risk prediction, especially in participants without prior history of cardiovascular disease.

Kidney vitality marker

Uromodulin also provides an indication of kidney vitality in other conditions. For example, individuals with impaired glucose metabolism, prediabetes or diabetes show significantly lower concentrations of serum uromodulin than healthy persons, indicating a risk of accompanying renal disease. In patients with systemic lupus erythematosus (SLE) uromodulin measurements can indicate nephritis. SLE-nephritis patients exhibit lower levels of serum uromodulin, while those without kidney involvement show levels comparable to healthy blood donors. Furthermore, uromodulin can be used to monitor patients undergoing long-term drug treatments or taking part in clinical drug trials to detect drug-induced nephrotoxicity, enabling drug doses to be adjusted accordingly.

Measurement of uromodulin

Uromodulin is traditionally determined in urine samples. However, the polymeric urinary form of the molecule causes preanalytical limitations, impairing the precision and reliability of the measurements. In serum, uromodulin is present in a stable form, most likely as a monomer, and serum measurements are highly reliable.

Uromodulin can be measured efficiently in serum or plasma using enzyme-linked immunosorbent assays (ELISA) based on microplates coated with anti-uromodulin antibodies. The patient uromodulin concentrations are established using a simple cut-off-based interpretation. External factors such as body weight, nutrition or muscle mass do not have to be factored into the results by additional calculations, as with classic markers. This makes it a fast, easy and sensitive test for the early identification of nephropathies and loss in renal function. ELISA is, moreover, suitable for high-throughput processing. Currently two commercial ELISAs are available for IVD determination of uromodulin in serum or plasma. The two ELISAs show a good correlation with each other.

Normal values for serum uromodulin were assessed using panels of healthy blood donors. Values were found to be higher in women than in men. In 190 healthy adult blood donors, the median value amounted to 188 ng/ml in males and 230 ng/ml in females. Children and adolescents exhibited comparable values to adults, with a median of 193 ng/ml observed in 443 healthy donors. The levels did not differ between girls and boys.

Perspectives

Uromodulin has enormous future potential as a universal marker of kidney health. It closes the diagnostic gaps of established kidney function markers, in particular for the early diagnosis of CKD. It is also a useful predictive marker for end-stage renal failure and renal graft outcome. Huge swathes of the global population are at increased risk of CKD due to rising prevalences of diabetes mellitus, obesity, hypertension and cardiovascular disease. Ageing populations will also result in more cases of CKD. Uromodulin testing will play a valuable future role in identifying and monitoring patients, and may help to limit the overall burden of kidney disease.

Figures and Tables

Figure 1. Synthesis and release of uromodulin

Figure 2. Uromodulin concentrations at different stages of CKD

Figure 3. Uromodulin as indicator of kidney graft vitality