news brief
ADA Endorses HbA1c for Diabetes Diagnosis In its newly released set of recommendations, “Standards of Medical Care in Diabetes–2010,” the American Diabetes Association (ADA) now officially recommends HbA1c testing for the diagnosis and monitoring of diabetes. This annually released document recommends new standards for the treatment of diabetes based on the latest scientific evidence. The report proposes a diagnosis of diabetes for HbA1c levels ≥6.5%, when testing is performed by a laboratory method certified by the National Glycohemoglobin Standardization Program and standardized to the Diabetes Control and Complications Trial assay. Other criteria for diagnosis include a fasting plasma glucose level of ≥126 mg/dL, a 2-hour plasma glucose level ≥200 mg/dL Snapshot Estimated Number of Newly Diagnosed Cases of Diabetes
Age Group
20–39
281
40–59
819
60+ 0
536 200
400
600
800 1000
Number of Cases (in thousands) Source: 2004–2006 National Health Interview Survey estimates projected to year 2007.
during an oral glucose tolerance test, and a random plasma glucose level of ≥200 mg/dL in patients with symptoms of hyperglycemia or a hyperglycemic crisis. The new standards also advise monitoring individuals with pre-diabetes on a yearly basis to prevent progression to full-blown diabetes. The ADA changed the name of a previous section of the report from “Diagnosis of pre-diabetes” to “Categories of increased risk for diabetes,” with the recommendation that HbA1c levels of 5.7%–6.4% be considered a sign for increased risk for future diabetes. In addition, the report suggests that HbA1c testing be performed at least twice per year in patients meeting treatment goals and quarterly for those who either have not meet their glycemic control goals or have recently changed therapy. A full copy of the ADA’s recommendations for this year are available at http://care.diabetesjournals. org/content/33/Supplement_1.
Clinical Laboratory News
The authoritative source for the clinical laboratorian
February 2010 volume 36, number 2 w w w. a a c c. o rg
An Optimistic Outlook for the Diagnostic Market What Will it Take to Succeed in a New Business Environment? By Bill Malone
I
n vitro diagnostics (IVD) manufacturers have good reason to feel like they are between a rock and a hard place. With the ‘Great Recession’ affecting every aspect of the U.S. economy and the tortuous path towards healthcare reform spreading uncertainty, IVD manufacturers have had to rethink their strategies as the second decade of the 21st century gets underway. But despite the murky beginnings of an economic recovery and the specter of an unwelcome mix of higher taxes on the industry and lower reimbursement for lab tests coming from Congress, the IVD market continues to grow. In a recent survey of medical device and IVD companies from Emergo Group, a consulting firm, 71% of executives said they expect overall sales to increase in 2010, and 70% said they felt very positive or somewhat positive about the overall business environment. With their fingers crossed that the early signs of economic recovery will continue, IVD manufacturers are preparing for steady, albeit slower growth while working harder than ever to hold onto decent prices for their products, according to industry observers. All too often for manufacturers, declining prices due to reimbursement hassles and competition mean that growth in testing eventually stops translating into growth in revenue. For this and other reasons, IVD companies are betting on strong returns from molecular diagnostics and advanced lab automation components to be profitable in a competitive and evolving business landscape. See IVD Market, continued on page 3
Emerging Biomarkers for Acute Kidney Injury
in this issue
Is There a Winner in the Offing? By Genna Rollins
A
cute kidney injury (AKI) is a complex, increasingly common syndrome, the diagnostics and treatments for which have remained essentially unchanged for decades, to the great frustration of clinicians and researchers. However, thanks to concerted efforts by key professional organizations, governmental agencies, and numerous research teams, considerable progress has been made since 2004. Now, many experts predict that the field is poised for transformation over the next decade. Novel urine and serum biomarkers will be central to this revolution in care. “The field of acute kidney injury rests upon development of new biomarkers,” explained Mark Okusa, MD, FASN, John C. Buchanan distinguished professor of medicine and chief of nephrology at the University of Virginia School of Medicine in Charlottesville. “We’re trying to find what cardiologists found with troponin I for acute coronary syndrome. Our goal is to find a kidney troponin I.” Okusa also is chair of the AKI advisory group for the American Society of Nephrology (ASN).
Changing Definitions, Terms Although definitions and even the nomenclature for AKI have changed over the years, the condition generally is recognized as the See Acute Kidney Injury, continued on page 6
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Uptick in Lab Spending Expected IVD Market, from page 1
“For 2009, we estimated a growth rate for the worldwide IVD market of approximately 5.3 percent, and for 2010, we’re projecting 6.1 percent growth,” said Gerard Conti, vice president at the healthcare market research firm Enterprise Analysis Corporation (EAC). “It makes sense that 2010 will be better for manufacturers because we see hospital budgets starting to thaw out, the credit crunch has eased up, and many hospitals put off big purchases that they can’t put off any longer.”
Ready to Spend Again? A huge drop in available credit for hospitals and other organizations, along with lower patient demand and increasing numbers of patients unable to pay for care, made the last 2 years some of the most difficult for IVD manufacturers. “In 2009, it was very difficult to win market share—customers tended to be fairly cautious, often deferring purchase decisions, and the capital expenditure environment was very limited,” explained Alan Harris, vice president for global marketing, chemistry systems, at Beckman Coulter. “Sectors like automation, where there is strong demand, stalled in that people didn’t have large capital budgets to deploy.” However, labs can only forestall purchases of needed equipment or upgrades to a certain point. “One year you can do without it, two becomes a strain, and three becomes a stretch,” Harris quipped. Eventually, labs that have deferred capital expenditures will have to buy; otherwise they could end up spending more on service than it would cost to replace an instrument. Even with recovery from the recession looking tenuous at best, there are signs that hospitals and other customers are beginning to have more funds to make the big purchases IVD manufacturers depend on, according to Rich Ramko, a medtech partner with Ernst & Young’s global life sciences division. “Lately we’ve seen more confidence from hospitals when it comes to issues like bad debt and capital expenditures,” he said. Even better, recent declines in the quality of the hospital payer mix seems to have finally flattened out, Ramko said, an important indicator of if and how much hospitals can expect to get paid. Commercial insurance usually pays the best, followed by Medicare and Medicaid. The most worrisome element—patients who pay out of pocket—can only be counted on about 20% of the time. “We’ve seen that percentage of Medicaid and uninsured go up over the last year or so, and lately that’s abated,” said Ramko. “But that payer mix will deteriorate again if unemployment goes up or stays where it is for a long time. People can only put off healthcare for so long, and after they wait, their ability to pay is even less than it was to begin with—their COBRA has run out, the medical situation is worse, and then uncompensated care at hospitals will rise.” Unemployment isn’t the only lingering concern that’s part of what Harris described as “macroeconomic overhang.” Outside the U.S., emerging markets may still suffer from devalued currencies that makes buying U.S. products more ex-
pensive, he explained. “Facing a significant economic downturn, every central bank began to dump liquidity, whether it was money supply, lower interest rates, or however they could better offset the global economic downturn.” With central banks pushing out this much cash, some currencies became greatly devalued and emerging markets—including Korea, South Africa, Turkey, and others—got hit hard. In other cases, the reverse was true when the dollar was comparatively low, bringing revenue for U.S.-based companies down with it. “While the actual quantity of products and services U.S. manufacturers delivered may have not changed dramatically, or may have even gone up, the amount of revenue that the global manufacturers received for that may have fluctuated significantly in certain countries because of changes in currency exchange rates,” said Harris.
Fighting the Price Plunge No matter how innovative their technology or how in sync their instruments are with the needs of laboratories, IVD manufacturers inevitably have to ask themselves the question: how do I hold onto a fair price? “The recurring theme we hear is, ‘how do you keep pricing from devolving’,” said Mark Hughes, also a vice president and senior consultant at EAC. “Manufacturers want to know how to charge a decent price and get reimbursement for their novel test that represents its true value so it doesn’t become a five dollar test.” Hughes and his colleagues find that more and more, companies are looking for solid evidence of the value of their tests by performing health economic studies.“More companies are now performing studies to try and prove that what they are bringing to market truly has value and that the test is displacing certain care protocols,” said Susan Farber, vice president of operations at EAC. “We are seeing more price pressure in diagnostics, so they’re trying to show that as part of the whole value stream, their test should be valued a little more highly than other products may have been in the past.” To get better reimbursement, manufacturers will have to demonstrate that a new test is truly an improvement over what’s on the market already, emphasized Ernst & Young’s Ramko. “If the demand is there, then the reimbursement will work itself out,” he said. “Those that show they can reduce the cost of care and are better than what’s currently available will get reimbursement and will be successful in the market. But if it’s a ‘me too’ product—you won’t see those products coming through to commercialization.”
Molecular Diagnostics Lead the Way While 4 to 5 years ago testing in the diabetes area helped to propel pre-recession annual market growth in the 8% range, now the diabetes share of the market has flattened out and left molecular testing as the leader in rapid growth. Part of this change has to do with the especially intense pricing pressure on diabetes testing, creating a counter-intuitive scenario with an exploding disease population but frozen revenues for testing. “We see the incidence and prevalence
of diabetes going through the roof, and it’s only going to get larger. Payers have done their best to mitigate the cost, and for a time, those techniques have been very effective,” said Harris. “But eventually quantity will trump price and the market will grow again. In this market you have to distinguish growth in testing versus revenue generated by it.” Molecular testing is also surpassing other areas of the IVD market by encroaching on territory that traditionally belonged to the microbiology lab, offering speed and turnaround times that traditional culture methods can’t match. “Rapid molecular tests to detect respiratory pathogens in hospitalized patients are new weapons to help control outbreaks of serious bacterial and viral infections, such as methicillinresistant Staphylococcus aureus (MRSA),” said Keith Chaitoff, divisional vice president, U.S. marketing of Abbott Diagnostics. “Healthcare-acquired infections are a major source of patient complications that increase lengths of stay and prolong recovery time.” Under pressure from payers, patients, and even Congress, hospitals need better solutions for managing healthcareacquired infections, with more and more facilities testing patients for bacterial and viral infections before admission. With fast and sensitive molecular tests, physicians get answers back in hours or a
day, not in the week to 10 days it can take for traditional microbe identification. This change in patient care will continue to drive the adoption of molecular methods, emphasized Jack Zakowski, director of scientific affairs and professional relations for Beckman Coulter. He offered the example of a respiratory panel. The physician would like to know whether an infection is viral or bacterial, and whether they can rule out the most serious illnesses. With traditional microbiology, the physician sends the sample to the microbiology lab—either hospital or reference lab-based—and waits for 1–3 days for bacterial identification or 5–10 days for myobacterial identification. “The clinical condition of the patient tends to answer the question much sooner than the laboratory in this situation,” Zakowski said. “We’re dealing with methodologies that are more than 100 years old—agar plates and Petri dishes—and the new molecular-based methods that are either in use today or that will be available in the next few years are going to transform that.” Zakowski thinks the biggest hurdle at this point may be the human one—getting people adapted to and comfortable with using the new technologies. Still, it will be challenges like MRSA that will create more demand. “This is all going to be driven by both an economic and clinical need,” See IVD Market, page 4
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he said. “These tests can make a huge difference in patient care and that will drive adoption of the technology.” The molecular diagnostic sector also tends to be more profitable than traditional microbiology, which is more of a commodity business and has lower margins, explained EAC’s Hughes. Molecular tests also command a much higher price per test, though in some instances the manufacturer has to pay patent royalties that eat into profits. “There has just been a continuing trend toward molecular testing, and some of that is taking away from traditional microbiology. Having said that, I don’t see traditional microbiology going away any time soon—we’re still going to be doing traditional culture plates for many years to come. But there are specific tests and areas where molecular is encroaching on traditional culture methods because of the speed and turnaround time advantages that it offers. So I think we’ll continue to see that eating away at some of the traditional microbiology.” EAC is projecting the microbiology market to grow at a steady 5% per year, while the molecular segment will see double-digit growth, between 12% and 14% per year. Hughes also predicted that manufacturers will continue to push for more simple instrumentation for their molecular tests, the ‘sample-in, answer-out’ model.
Labs Still Hungry for Automation IVD manufacturers will also continue to push hard to get laboratorians the automation solutions they need to cope with more complex, consolidated operations as well as lingering staffing shortages. Just taking a look at exhibit halls and conference programs demonstrates both the enthusiasm and challenges laboratorians have with automation. “In coping with cost pressures and personnel shortages, laboratories increasingly are being forced to do more with less,” said Abbott’s Chaitoff. “This is fueling development and market share growth of highly automated analyzers with automated sampling handling features and sophisticated informatics to improve throughput, results reporting, and coordination with the LIS.” Beckman Coulter’s Zakowski echoed this assessment. “The technology is advancing rapidly, and I think you’ll see automation become better, cheaper, and faster— and that’s true whether we’re talking about the analyzers themselves, the kinds of assays they can perform, the kind of track lines they’re connected to, or the information technology,” he said. “We’re doing things now we didn’t dream of 10 years ago, and I think that will be the case 10 years from now.” Prices are already coming down, with a handful of companies that are very competitive and willing to cut an amazing deal to place an automation solution, noted EAC’s Farber. Manufacturers know that if they can get their automation solution in, they tend to have a hold on that lab’s business. “I’ve heard of some ridiculously lowpriced deals where pieces of automation were practically given away,” said Farber. As a result, she thinks it’s possible that, in terms of dollar investment, the market for auto-
Clinical Laboratory News February 2010
mation could start to flatten out eventually; however, with regard to the number of labs that are looking to move toward automation, “that’s still a very strong number,” she indicated. “From what I’ve seen in the last few months, laboratorians are quite serious about automation and about standardization on automation, so I think there is still a very good outlook for this market.” Advanced analyzers, more molecular testing, and more automation will all lead to dramatic changes in what the clinical lab looks like, emphasized Beckman Coulter’s Harris. “The chem-immuno line will become the chem-immuno-coag-hematology
line over time, and likewise, those individual disciplines that have remained relatively separate in specialty labs, like microbiology, flow cytometry, and molecular tests, will all benefit from more automation and more specific and sensitive techniques, so I think that’s a good view of our future.”
Point-of-Care Market Faces Hurdles Another area of growth in the IVD market is coming from point-of-care testing (POCT), which EAC projects will grow in the range of 7%–8% per year for the next few years. While the firm’s consultants noted a strong desire on the part of providers to move testing out to decentralized locations, POCT still hasn’t met the growth expectations that investors and analysts initially expected.
AdvaMed Launches AdvaMed Dx for Diagnostics Companies After years of debate among in vitro diagnostic (IVD) companies about how best to work together to advocate for the industry, a new association under the auspices of the Advanced Medical Technology Association (AdvaMed) is creating enthusiasm among IVD companies as they look toward coping with changes in healthcare reform in the years ahead. “This is a particularly sensitive period, where we’ve had healthcare reform running the profile of many aspects of our industry from a government affairs standpoint,” said Scott Garrett, Beckman Coulter’s chairman, president, and CEO, who will serve as chair of the AdvaMed Dx board of directors. “We also have new regulatory issues coming out of China, and a continual emphasis on Japan and Europe. It’s an important time where it will be very helpful to get senior executives throughout diagnostics very involved in the association.” AdvaMed Dx will work as an association-within-an-association, where the new organization can take advantage of the staff and capabilities of AdvaMed while still focusing exclusively on issues that matter to the IVD industry. With AdvaMed covering such a large spectrum of companies—manufacturers of everything from stents to orthopedics and wound care products—Garrett sees AdvaMed Dx as a way for IVD companies to have a strong voice on issues and perspectives that are unique to their industry. “It’s our expectation that the positions and issues of AdvaMed Dx will rarely be in conflict with the rest of AdvaMed, but they might often be different than the priorities or agenda of AdvaMed,” said Garrett. “Though it would be great to have an independent global diagnostics organization, our industry is relatively small, and the level of infrastructure and staff that we could afford as a completely separate organization is probably not significant enough for us to have a strong voice. So I think this approach is the best of both worlds.” Issues of particular importance to the new association will include following FDA regulation of diagnostic tests and working to curb any further cuts to the lab fee schedule. With a lot of new people in the FDA office, Garrett expects AdvaMed Dx to help companies establish a closer relationship with the agency. “FDA is under pressure to be tougher— pressure from the public and from Congress,” he said. “So we have an opportunity to improve their understanding of all that goes on in the industry in a way that is more balanced than what they might have picked up so far. But I have a lot of confidence that the new FDA leadership is quite capable and has the right objectives in mind.” In working with the Center for Medicare and Medicaid Services (CMS), AdvaMed Dx will have a chance to do a lot better for the IVD industry than what has been done before, Garrett said. “We want to make sure that our customers, the labs and the hospitals in the U.S., are reimbursed fairly for the services they provide in the lab,” he said. “I think there will probably be an opportunity over the coming years to take a good hard look at the lab fee schedule and try and get it in line with reality.” Garrett expects the new organization to get off to a fast start this year, and said he’s been encouraged by the level of enthusiasm from the major diagnostics companies. “We expect AdvaMed Dx to be an important part of our industry in the future,” he said.
While certain segments of the POCT market have expanded rapidly, such as rapid testing for the 2009 H1N1 virus, POCT certainly cannot substitute for all core lab tests. “Point-of-care has to balance a lot of things: turnaround, precision and accuracy, and cost-per-test, and I don’t see the technology there yet for point of care to take over as much as people are predicting,” said Beckman Coulter’s Zakowski. “The increased cost of POCT has to be trumped by some workflow advantage within the site of care, or it can’t be successful.” Essentially, the test must help the hospital move the patient forward in a meaningful way, such as blood gas in intensive care units or coagulation tests in emergency departments and operating rooms. These kinds of tests allow clinicians to test and treat more efficiently, and have moved forward at an ambitious rate, Zakowski said. However, a manufacturer must study the cycle of care attentively if it wants to make the extra dollar or so for a POC test to be worth it. For instance, with blood gas testing, clinicians might actually need blood gas, basic metabolic panel and lactate results before they’re comfortable moving the patient forward, explained Zakowski. So just offering the quick blood gas will, in some situations, do nothing for clinicians because they still have to wait for the other tests from the main lab. It can actually make the workflow more complicated because clinicians have to look for answers from two separate places. “I think POCT is a promising piece of the market, but it has some very particular demands,” he said. “And it’s not really taking from main lab volumes, but mostly complementary, in fact. So it’s an opportunity more than a threat for the main lab.” POCT is also a hot area for startup companies with many of them developing POCT multiplexing platforms that use disposable cartridges—some in hematology, and even in the molecular area, noted the consultants from EAC. Hughes and Farber indicated that technology has by no means peaked for POCT, considering all the promising innovations at these new companies. According to Abbott’s Chaitoff, the ability of manufacturers to pull out all the stops in POCT technology is what will make the difference in the marketplace of the future. “Whether we are talking about POCT, molecular, or traditional core lab diagnostics, the key is that advanced technology— microfluidics, nanotechnology, advanced chemistries, biologic breakthroughs, and information sciences—all are going to have to converge more and more to achieve goals around productivity, outcomes, and physician and patient satisfaction,” he said. “And yes, reduced overall healthcare costs.”
cine. And manufacturers want to be sure they get a piece of the action when the field matures. “While the 20th Century witnessed an unprecedented growth in the development of medications and therapies, this century will witness a similar explosion in the development of diagnostic tests,” said Abbott’s Chaitoff. “Human blood is overflowing with molecules and proteins that each have a story to tell. Until recently, we had very limited knowledge of what these molecules and proteins did. Advanced diagnostics will lead to a wider recognition of the value of the lab and diagnostics to solve many of our pressing healthcare needs from optimizing patient care to reduce the financial burden on the healthcare system.” Ironically, the federal government’s drive to eliminate waste and reduce the
amount of reimbursement will turn into an advantage for pharmacogenomic tests if manufacturers play their cards right, said Ernst & Young’s Ramko. The challenge will be to prove to payers that advanced tests really do make a difference in care, reduce costs, and therefore deserve reimbursement themselves. “With big pharma developing fewer small-molecule type drugs and moving to more expensive biologics, there will be an emphasis on making sure that a treatment will really work,” he said. “Clearly the push is going to be to reduce costs, to not pay for things that are unnecessary. As the move to reduce cost is more and more acute, suppliers of treatments are going to need pharmacogenomics to prove how a therapy can work for certain targeted individuals instead of offering it to everybody to see what works.”
Pharmaceutical companies will be using pharmacogenomics in the research and development phase of drugs and as a tool to show the government and other payers why they should get reimbursement, Ramko emphasized. And just like more mature sectors of the IVD market, manufacturers will have to put a focused effort into proving the value of a new test for this purpose. Although widespread use of pharmacogenomic tests has not yet arrived, manufacturers want to make sure that they’re not left out when the time comes, said EAC’s Farber. “People are really starting to come to grips with the reality of companion diagnostics, and we’re now getting very serious inquiries about where the market is going and how a company can position itself CLN to do something about it.”
Still Betting on Pharmacogenomics Part of the surprisingly positive outlook for the overall IVD market draws from the consensus among laboratorians and IVD companies that in the final analysis, diagnostics can improve both healthcare quality and cost-effectiveness. Of course, this is in spite of the way payment policy handed down from Congress and the Center for Medicare and Medicaid Services (CMS) rarely seems to recognize this fact. For many, pharmacogenomics symbolizes the way in which advances in diagnostics can have a big impact on the future of medi-
Clinical Laboratory News February 2010
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Serum Creatinine Inadequate Measure Acute Kidney Injury, from page 1
abrupt loss of kidney function that leads to fluid retention, accumulation of metabolic waste products, and dysregulation of extracellular volume and electrolytes. Common causes of AKI range from decreased renal perfusion and contrast-induced nephropathy to sepsis and nephrotoxicity from medications such as aminoglycoside antibiotics and non-steroidal anti-inflammatory drugs. AKI now is the preferred term over acute renal failure, to emphasize the range of AKI disease from early injury to progressive loss of function requiring renal replacement therapy. Two classification systems for the condition proposed in recent years are gaining acceptance. Both rely on changes in serum creatinine levels and urine output. The Acute Kidney Injury Network (AKIN) defined AKI as an reduction in kidney function within 48 hours, involving an absolute increase in serum creatinine of ≥0.3 mg/dL, a percentage increase of ≥50% or 1.5 times above baseline, or documented oliguria of less than 0.5 ml/Kg per hour for more than 6 hours. Meanwhile, the Acute Dialysis Quality Initiative issued the Risk, Injury, Failure, Loss and End-stage (RIFLE) criteria, which use graded increases in glomerular filtration rate based on serum creatinine levels and weightdependent urine output parameters. Nationally, AKI accounts for at least 3%–4% of all hospitalizations and may be a contributing factor in more than onethird of all admissions, at a cost of about $10 billion annually. At the same time, the incidence of AKI in the community is rising, with an estimated rate of 500 per 100,000 population in 2002, up from approximately 61 per 100,000 population in 1988. Adding to the magnitude of these figures, 20%–30% of critically ill patients develop AKI, and depending on the patient population, mortality following an episode of AKI is estimated to be between 40% and 60%. Validation of both the AKIN and RIFLE systems has underscored the important effects of small declines in glomerular filtration rate on the overall outcome of critically ill patients, according to Okusa. “Even the least severe categories, ‘R’ in RIFLE or AKIN stage I, have been associated with a mortality rate of approximately 30 percent,” he indicated. In addition, recent research has changed the thinking about the natural course of AKI. “Previously kidney function was gen-
For Further Information Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury, http://ccforum.com/content/11/2/ R31 Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group, http://ccforum.com/content/8/4/ R204 Kidney Disease: Improving Global Outcomes, www.kdigo.org
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erally thought to completely return to normal, but information now suggests that the long-term course for a significant number of patients with AKI is high-stage chronic kidney disease,” noted Paul Kimmel, MD, senior advisor in the Division of Kidney, Urologic and Hematologic Diseases at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). “AKI seems to go on to progressive injury, and the idea now is that there is a spectrum of functional kidney responses after AKI.” Kimmel also is project scientist for the NIDDK-funded Assessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESSAKI) research initiative.
A Lackluster Gold Standard Even as research is elucidating the pathology of and outcomes associated with AKI, treatment advances have been hampered by lack of sensitive and specific biomarkers for the condition. Although it is still considered the gold standard, serum creatinine is “far from an ideal parameter,” according to Norbert Lameire, MD, emeritus professor of medicine at the University of Gent, Belgium, and co-chair of the Kidney Disease: Improving Global Outcomes clinical practice guidelines on AKI. “In AKI it takes at least 24 hours, and in many cases, 48 hours, before you see a significant increase in serum creatinine. So you lose this crucial, let’s say 36 hours, in which a lot of injury has gone on before you see it in your serum creatinine.” As much as 50% of kidney function can be lost by the time serum creatinine levels reach abnormal levels. Serum creatinine also is affected by nonrenal factors, such as protein intake, muscle mass, age, and sex, and it is not sensitive to kidney insults that do not affect filtration. Until recently, these biological variances were compounded by analytical challenges, but over the past several years considerable industry-wide effort has gone into standardization and commutability of serum creatinine measurements. All-in-all, these shortcomings have had the compound effect of not only holding back treatment advances but also delaying anti-AKI drug development. A series of summits in 2004, sponsored by the ASN and with participation from NIDDK, FDA, and other professional associations, highlighted that reliance on serum creatinine was “stifling therapeutic progress,” according to Chirag Parikh, MD, PhD, associate professor of medicine at Yale University School of Medicine. “People realized we’d not made any progress in terms of patient care and morbidity and mortality of AKI. Serum creatinine was not only hindering diagnosis and treatment, but it was weakening the drug development process.” Earlier, more sensitive biomarkers would enable physicians to fine-tune the basics of AKI treatment—blood pressure management along with reperfusion and vasopression therapy—and enable them to start dialysis earlier when needed. Above all, better biomarkers ultimately would lead to development of drugs that would halt quickly the progression of AKI.
Unprecedented Enthusiasm Since the 2004 summits, research has accelerated rapidly, to the point that some pro-
Clinical Laboratory News February 2010
Tracking the Course of Acute Kidney Injury Landmark Study Will Evaluate New Markers Although numerous potential biomarkers for acute kidney injury (AKI) have been identified and investigated—many with favorable performance profiles—the candidate markers need further evaluation in larger, more diverse populations for longer periods of time in order to achieve breakthroughs in AKI care. A major National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) initiative seeks to do just that. Assessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) is a landmark study that will follow for a mean of 3 years a diverse population of 1,200 patients in a range of clinical settings at three participating centers. ASSESS-AKI has two primary goals: determining whether hospitalized patients with an episode of AKI are at greater risk of developing chronic kidney disease than patients without AKI, after adjusting for pre-existing levels of kidney function and potential confounders; and determining whether these AKI patients are at higher risk for death, cardiovascular and other adverse events after hospitalization than control subjects. “Our purpose is two-fold. One is to provide more information about the natural history of AKI, particularly acute tubular necrosis in hospitalized patients,” explained ASSESS-AKI project scientist Paul Kimmel, MD, who also is senior advisor in the Division of Kidney, Urologic and Hematologic Diseases at NIDDK. “The other is to develop our understanding of how biomarkers can help in predicting outcomes, specifically longterm kidney response in patients who develop AKI.” ASSESS-AKI began enrolling patients in December 2009; outcomes from the trial are expected by the end of 2013. Evaluating currently used and novel biomarkers will be a key aspect of the study. At least five unique blood and urine samples will be collected over the course of 3 years from 600 patients with AKI and 600 matched controls. A minimum of 16 novel urine and 10 novel serum biomarkers will be measured, in addition to standard tests such as urine and serum creatinine, blood urea nitrogen, urine and blood albumin, calcium, and glucose, among others. “It’s quite likely, because we’ll have enough patients, statistical power, and tests, that we’ll be able to find any relationships between new biochemical assays and long-term outcomes that may exist,” said Kimmel. ASSESS-AKI’s precise sample collection, handling and storage protocols also are expected to advance the AKI evidence base, according to Kimmel. “One of the things we’re trying to do is to put our measurements into a clinical context. So if we learn that urine has to be handled in a certain way or we lose certain markers, but find that there’s a six hour delay until it’s processed in a standardized manner in all the study’s different clinical sites, that will be very important. The utility of something that has to be collected under extremely specified conditions will be less generalizable.” posed biomarkers are tantalizingly close to being implemented in clinical practice. “There’s now unprecedented enthusiasm in nephrology for early AKI biomarker detection research,” observed Parikh. “There is a pipeline of development full of numerous possibilities and it is very likely a test or tests will come from that pipeline that are good enough to replace the current paradigm of care.” A review he conducted in 2008 identified 21 serum and urine biomarkers of AKI that had utility in the differential diagnosis, early detection and/ or prognosis of the condition (Kidney Int 2008;73:1008–16). These markers also have been associated with injury to specific segments of the kidney nephron, such as the proximal and distal tubules, Loop of Henle, and collecting ducts, placing them in the realm of structural indicators of injury in contrast to serum creatinine’s role as a functional parameter. Of the many potential markers, neutrophil gelatinase-associated lipocalin (NGAL) is at the top of many researchers’ lists. Also known as lipocalin-2 or siderocalin, NGAL is a protein in neutrophils that rises within 2–4 hours after kidney injury. Arguably the most studied emerging marker of AKI,
NGAL has been investigated across a broad range of clinical settings, including post-cardiac surgery, critical and emergency care, as well as in adult and pediatric populations. A recent meta-analysis of 19 studies involving more than 2,500 patients found that the area under the curve/receiver operating characteristic of NGAL to predict AKI overall was 0.815, 0.775 in cardiac surgery patients, 0.728 in critically ill patients, and 0.894 following contrast infusion, respectively (Am J Kidney Dis 2009;54:1012–24). NGAL showed better predictive ability in children than adults, and it appeared to be useful in predicting renal replacement therapy and, to some extent, in-hospital mortality. “Our analysis found that NGAL appears to have diagnostic value for early AKI and prognostic value for renal replacement therapy and mortality, both overall and across a range of subgroups,” said lead author Michael Haase, MD, assistant professor of nephrology and intensive care medicine at Charité-University Medicine Berlin in Germany.
The Need for More Data As promising as this analysis appeared to be, it highlighted the challenge facing implementation of all the AKI biomarkers under
Proposed Biomarkers of Acute Kidney Injury Numerous biomarkers have been proposed for the differential diagnosis, early detection and prognosis of patients with AKI.
Differential Diagnosis in Established AKI Serum Markers ® Carbamylated hemoglobin (carb Hb) ® Cystatin C ® Neutrophil gelatinase-associated lipocalin (NGAL) Urine Markers ® α-1 microglobulin ® Glutathione-S-transferase (GST) ® Interleukin-18 (IL-18) ® Kidney injury molecule-1 (KIM-1) ® N-acetyl-β-D-glucosaminidase (NAG) ® NGAL ® Sodium hydrogen exchanger 1 (NHE3) ® Matrix metalloproteinase-9 (MMP-9)
Early Detection of AKI Serum Markers ® Cystatin C ® Prohormone of atrial natriuretic peptide (ProANP) ® Neutrophil-CD11b ® NGAL Urine Markers ® α-GST ® γ-glutamyl transpeptidase ® π-GST ® Alkaline phosphatase ® GST ® KIM-1 ® IL-18 ® Lactate dehydrogenase (LDH) ® NAG ® NGAL ® MMP-9
Prognosis of AKI Serum Markers ® Cystatin C ® IL-6 ® IL-8 ® IL-10 ® NGAL Urine Markers ® α-1 microglobulin ® α-GST ® β-2 microglobulin ® Cystatin C ® γ-glutamyltransferase ® IL-18 ® KIM-1 ® LDH ® NAG ® NGAL ® Retinol-binding Protein Adapted from Coca, SG, Yalavarthy, R, Concata, J, and Parikh, CR, Kidney Intl 2008;73:1008-16.
investigation. Most importantly, there has yet to be a prospective validation study in a large number of patients with different causes of AKI. The majority of studies have been in small populations or single centers examining AKI in one setting or clinical circumstance, such as post-cardiac surgery or in critically ill children. In addition, with NGAL and various other proposed biomarkers, a variety of test platforms have been used with different protocols and reference ranges. For instance, the majority of studies identified in Haase’s meta-analysis used CLIA-waived ELISAs, with NGAL reference ranges for the non-AKI control populations varying from 600 U/L elevated
