Clinical Laboratory News - Feb 2010

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ADA ENDORSESHBA1C

FORDIABETESDIAGNOSIS

In its newly released set of recom-mendations, Standards of MedicalCare in Diabetes2010, the Ameri-can Diabetes Association (ADA)now officially recommends HbA1c

testing for the diagnosis and moni-toring of diabetes. This annuallyreleased document recommendsnew standards for the treatment ofdiabetes based on the latest scien-tific evidence.

The report proposes a diagno-sis of diabetes for HbA1c levels6.5%, when testing is performedby a laboratory method certifiedby the National Glycohemoglo-bin Standardization Programand standardized to the DiabetesControl and Complications Trialassay. Other criteria for diagnosisinclude a fasting plasma glucose

level of 126 mg/dL, a 2-hourplasma glucose level 200 mg/dL

during an oral glucose tolerancetest, and a random plasma glucoselevel of 200 mg/dL in patientswith symptoms of hyperglycemiaor a hyperglycemic crisis. The newstandards also advise monitoringindividuals with pre-diabetes on ayearly basis to prevent progressionto full-blown diabetes.

The ADA changed the name of aprevious section of the report fromDiagnosis of pre-diabetes toCategories of increased risk for di-abetes, with the recommendationthat HbA1c levels of 5.7%6.4% beconsidered a sign for increased risk

for future diabetes. In addition, thereport suggests that HbA1c testingbe performed at least twice peryear in patients meeting treatmentgoals and quarterly for those whoeither have not meet their glycemiccontrol goals or have recentlychanged therapy.

A full copy of the ADAs recom-mendations for this year are avail-able at http://care.diabetesjournals.org/content/33/Supplement_1.

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FEBRUARY 2010VOLUME 36, NUMBER 2

w w w . a a c c . o r g

An Optimistic Outlook forthe Diagnostic MarketWhat Will it Take to Succeedin a New Business Environment?BYBILLMALONE

In vitro diagnostics (IVD) manufacturers have good reasonto feel like they are between a rock and a hard place. With theGreat Recession affecting every aspect of the U.S. economyand the tortuous path towards healthcare reform spreadinguncertainty, 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 andthe specter of an unwelcome mix of higher taxes on the industryand lower reimbursement for lab tests coming from Congress, theIVD market continues to grow. In a recent survey of medical deviceand 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 theoverall business environment.

With their fingers crossed that the early signs of economic re-covery 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 toindustry observers. All too often for manufacturers, declining prices due to reimbursement hassles and compe-tition mean that growth in testing eventually stops translating into growth in revenue. For this and other rea-sons, IVD companies are betting on strong returns from molecular diagnostics and advanced lab automationcomponents to be profitable in a competitive and evolving business landscape.

Emerging Biomarkers

for Acute Kidney InjuryIs There a Winner in the Offing?BYGENNAROLLINS

Acute kidney injury (AKI) is a complex, increasingly common syndrome, the diagnostics and treat-ments for which have remained essentially unchanged for decades, to the great frustration ofclinicians and researchers. However, thanks to concerted efforts by key professional organizations,governmental agencies, and numerous research teams, considerable progress has been made since2004. 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. Buchanandistinguished professor of medicine and chief of nephrology at the

University of Virginia School of Medicine in Charlottesville. Weretrying to find what cardiologists found with troponin I for acute coro-nary syndrome. Our goal is to find a kidney troponin I. Okusa also ischair of the AKI advisory group for the American Society of Nephrol-ogy (ASN).

Changing Definitions, Terms

Although definitions and even the nomenclature for AKI havechanged over the years, the condition generally is recognized as the

See IVD Market, continued on page 3

See Acute Kidney Injury, continued on page 6

IN THIS ISSUE

Lab 2010

8Preeclampsia Diagnosis& Management11Expert Access:Infectious Diseases12Regulatory Profiles

13Industry Profiles

14Diagnostic Profiles

15News from the FDA

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GREENFIELD,OH

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ClinicalLaboratoryNewsTheAmericanAssociationforClinicalChemistry,Inc.1850KStreet,NW,Suite625

Washington,DC20006

SNAPSHOTEstimated Number of Newly Diagnosed

Cases of Diabetes

Source: 20042006 National Health InterviewSurvey estimates projected to year 2007.

Number of Cases(in thousands)

2039

4059

60+

0 200 400 600 800 1000

Age

Group

281

819

536
http://care.diabetesjournals.org/content/33/Supplement_1http://care.diabetesjournals.org/content/33/Supplement_1http://care.diabetesjournals.org/content/33/Supplement_1http://care.diabetesjournals.org/content/33/Supplement_1


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3/16CLINICALLABORATORYNEWS FEBRUARY2010 3

For 2009, we estimated a growth ratefor the worldwide IVD market of approxi-mately 5.3 percent, and for 2010, wereprojecting 6.1 percent growth, said GerardConti, vice president at the healthcare mar-ket research firm Enterprise Analysis Cor-poration (EAC). It makes sense that 2010will be better for manufacturers because we

see hospital budgets starting to thaw out,the credit crunch has eased up, and manyhospitals put off big purchases that theycant put off any longer.

Ready to Spend Again?

A huge drop in available credit for hospitalsand other organizations, along with lowerpatient demand and increasing numbersof patients unable to pay for care, made thelast 2 years some of the most difficult forIVD manufacturers. In 2009, it was verydifficult to win market sharecustomerstended to be fairly cautious, often defer-ring purchase decisions, and the capital

expenditure environment was very lim-ited, explained Alan Harris, vice presidentfor global marketing, chemistry systems,at Beckman Coulter. Sectors like automa-tion, where there is strong demand, stalledin that people didnt have large capitalbudgets to deploy. However, labs can onlyforestall purchases of needed equipmentor upgrades to a certain point. One yearyou can do without it, two becomes astrain, and three becomes a stretch, Harrisquipped. Eventually, labs that have deferredcapital expenditures will have to buy; oth-erwise they could end up spending moreon service than it would cost to replace an

instrument.Even with recovery from the recession

looking tenuous at best, there are signs thathospitals and other customers are begin-ning to have more funds to make the bigpurchases IVD manufacturers dependon, according to Rich Ramko, a medtechpartner with Ernst & Youngs global lifesciences division. Lately weve seen moreconfidence from hospitals when it comesto issues like bad debt and capital expendi-tures, he said.

Even better, recent declines in the qual-ity of the hospital payer mix seems to havefinally flattened out, Ramko said, an im-

portant indicator of if and how much hos-pitals can expect to get paid. Commercialinsurance usually pays the best, followed byMedicare and Medicaid. The most worri-some elementpatients who pay out ofpocketcan only be counted on about20% of the time. Weve seen that percent-age of Medicaid and uninsured go up overthe last year or so, and lately thats abated,said Ramko. But that payer mix will dete-riorate again if unemployment goes up orstays where it is for a long time. People canonly put off healthcare for so long, and af-ter they wait, their ability to pay is even lessthan it was to begin withtheir COBRA

has run out, the medical situation is worse,and then uncompensated care at hospitalswill rise.

Unemployment isnt the only linger-ing concern thats part of what Harris de-scribed as macroeconomic overhang.Outside the U.S., emerging markets maystill suffer from devalued currencies thatmakes buying U.S. products more ex-

pensive, he explained. Facing a signifi-cant economic downturn, every centralbank began to dump liquidity, whether itwas money supply, lower interest rates, orhowever they could better offset the globaleconomic downturn. With central bankspushing out this much cash, some curren-cies became greatly devalued and emergingmarketsincluding Korea, South Africa,

Turkey, and othersgot hit hard.In other cases, the reverse was true when

the dollar was comparatively low, bringingrevenue for U.S.-based companies downwith it. While the actual quantity of prod-ucts and services U.S. manufacturers deliv-ered may have not changed dramatically,or may have even gone up, the amountof revenue that the global manufacturersreceived for that may have fluctuated sig-nificantly in certain countries because ofchanges in currency exchange rates, saidHarris.

Fighting the Price Plunge

No matter how innovative their technologyor how in sync their instruments are withthe needs of laboratories, IVD manufac-turers inevitably have to ask themselves thequestion: how do I hold onto a fair price?The recurring theme we hear is, how doyou keep pricing from devolving, saidMark Hughes, also a vice president andsenior consultant at EAC. Manufacturerswant to know how to charge a decent priceand get reimbursement for their novel testthat represents its true value so it doesntbecome a five dollar test.

Hughes and his colleagues find thatmore and more, companies are looking for

solid evidence of the value of their tests byperforming health economic studies. Morecompanies are now performing studies totry and prove that what they are bringingto market truly has value and that the test isdisplacing certain care protocols, said Su-san Farber, vice president of operations atEAC. We are seeing more price pressure indiagnostics, so theyre trying to show thatas part of the whole value stream, their testshould be valued a little more highly thanother products may have been in the past.

To get better reimbursement, manu-facturers will have to demonstrate thata new test is truly an improvement over

whats on the market already, emphasizedErnst & Youngs Ramko. If the demand isthere, then the reimbursement will workitself out, he said. Those that show theycan reduce the cost of care and are betterthan whats currently available will get re-imbursement and will be successful in themarket. But if its a me too productyouwont see those products coming throughto commercialization.

Molecular Diagnostics Lead the Way

While 4 to 5 years ago testing in the diabe-tes area helped to propel pre-recession an-nual market growth in the 8% range, now

the diabetes share of the market has flat-tened out and left molecular testing as theleader in rapid growth. Part of this changehas to do with the especially intense pric-ing pressure on diabetes testing, creating acounter-intuitive scenario with an explod-ing disease population but frozen revenuesfor testing.

We see the incidence and prevalence

of diabetes going through the roof, and itsonly going to get larger. Payers have donetheir best to mitigate the cost, and for atime, those techniques have been very ef-fective, said Harris. But eventually quan-tity will trump price and the market willgrow again. In this market you have to dis-tinguish growth in testing versus revenuegenerated by it.

Molecular testing is also surpassing oth-er areas of the IVD market by encroachingon territory that traditionally belonged to

the microbiology lab, offering speed andturnaround times that traditional culturemethods cant match. Rapid moleculartests to detect respiratory pathogens inhospitalized patients are new weapons tohelp control outbreaks of serious bacterialand viral infections, such as methicillin-resistant Staphylococcus aureus (MRSA),said Keith Chaitoff, divisional vice presi-dent, U.S. marketing of Abbott Diagnos-tics. Healthcare-acquired infections are amajor source of patient complications thatincrease lengths of stay and prolong re-covery time. Under pressure from payers,patients, and even Congress, hospitals need

better solutions for managing healthcare-acquired infections, with more and morefacilities testing patients for bacterial andviral 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 takefor traditional microbe identification. Thischange in patient care will continue todrive the adoption of molecular methods,emphasized Jack Zakowski, director of sci-entific affairs and professional relations forBeckman Coulter. He offered the exampleof a respiratory panel. The physician wouldlike to know whether an infection is viral orbacterial, and whether they can rule out themost serious illnesses. With traditional mi-crobiology, the physician sends the sample

to the microbiology labeither hospitalor reference lab-basedand waits for 13days for bacterial identification or 510days for myobacterial identification.

The clinical condition of the patienttends to answer the question much soon-er than the laboratory in this situation,Zakowski said. Were dealing with meth-odologies that are more than 100 yearsoldagar plates and Petri dishesand thenew molecular-based methods that are ei-ther in use today or that will be available inthe next few years are going to transformthat. Zakowski thinks the biggest hurdle atthis point may be the human onegetting

people adapted to and comfortable withusing the new technologies. Still, it will bechallenges like MRSA that will create moredemand. This is all going to be drivenby both an economic and clinical need,

See IVD Market, page 4

The Assay You Can Trust...

Uptick in Lab Spending ExpectedIVD Market, from page 1
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4/164 CLINICALLABORATORYNEWS FEBRUARY2010

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Amy Saenger, PhDMayo Clinic, Rochester, Minn.

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he said. These tests can make a huge dif-ference in patient care and that will driveadoption of the technology.

The molecular diagnostic sector alsotends to be more profitable than tradi-tional microbiology, which is more of acommodity business and has lower mar-gins, explained EACs Hughes. Molecular

tests also command a much higher priceper test, though in some instances themanufacturer has to pay patent royaltiesthat eat into profits. There has just beena continuing trend toward molecular test-ing, and some of that is taking away fromtraditional microbiology. Having said that,I dont see traditional microbiology goingaway any time soonwere still going to bedoing traditional culture plates for manyyears to come. But there are specific testsand areas where molecular is encroachingon traditional culture methods because ofthe speed and turnaround time advantagesthat it offers. So I think well continue to

see that eating away at some of the tradi-tional microbiology. EAC is projecting themicrobiology market to grow at a steady5% per year, while the molecular segmentwill see double-digit growth, between 12%and 14% per year. Hughes also predictedthat manufacturers will continue to pushfor more simple instrumentation for theirmolecular tests, the sample-in, answer-outmodel.

Labs Still Hungry for Automation

IVD manufacturers will also continue topush hard to get laboratorians the automa-tion solutions they need to cope with more

complex, consolidated operations as wellas lingering staffing shortages. Just takinga look at exhibit halls and conference pro-grams demonstrates both the enthusiasmand challenges laboratorians have withautomation. In coping with cost pressuresand personnel shortages, laboratories in-creasingly are being forced to do more withless, said Abbotts Chaitoff. This is fuelingdevelopment and market share growth ofhighly automated analyzers with automat-ed sampling handling features and sophis-ticated informatics to improve throughput,results reporting, and coordination withthe LIS.

Beckman Coulters Zakowski echoedthis assessment. The technology is advanc-ing rapidly, and I think youll see automa-tion become better, cheaper, and fasterand thats true whether were talking aboutthe analyzers themselves, the kinds of assaysthey can perform, the kind of track linestheyre connected to, or the informationtechnology, he said. Were doing thingsnow we didnt dream of 10 years ago, andI think that will be the case 10 years fromnow.

Prices are already coming down, with ahandful of companies that are very com-petitive and willing to cut an amazing deal

to place an automation solution, notedEACs Farber. Manufacturers know that ifthey can get their automation solution in,they tend to have a hold on that labs busi-ness. Ive heard of some ridiculously low-priced deals where pieces of automationwere practically given away, said Farber. Asa result, she thinks its possible that, in termsof dollar investment, the market for auto-

mation could start to flatten out eventually;however, with regard to the number of labsthat are looking to move toward automa-tion, thats still a very strong number, sheindicated. From what Ive seen in the lastfew months, laboratorians are quite seriousabout automation and about standardiza-tion on automation, so I think there is still avery good outlook for this market.

Advanced analyzers, more moleculartesting, and more automation will all leadto dramatic changes in what the clinical lablooks like, emphasized Beckman CoultersHarris. The chem-immuno line will be-come the chem-immuno-coag-hematology

line over time, and likewise, those individ-ual disciplines that have remained relativelyseparate in specialty labs, like microbiology,flow cytometry, and molecular tests, will allbenefit from more automation and morespecific and sensitive techniques, so I thinkthats a good view of our future.

Point-of-Care Market Faces Hurdles

Another area of growth in the IVD market iscoming 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 firms consultants noted a strongdesire on the part of providers to move test-ing out to decentralized locations, POCTstill hasnt met the growth expectations thatinvestors and analysts initially expected.

Lab Automation Now More AffordableIVD Market, from page 3

AdvaMed Launches AdvaMed Dxfor 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 associa-

tion under the auspices of the Advanced Medical Technology Associa-

tion (AdvaMed) is creating enthusiasm among IVD companies as theylook toward coping with changes in healthcare reform in the years

ahead.

This is a particularly sensitive period, where weve had healthcare

reform running the profile of many aspects of our industry from a gov-

ernment affairs standpoint, said Scott Garrett, Beckman Coulters chair-

man, 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. Its 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 capa-

bilities of AdvaMed while still focusing exclusively on issues that matter

to the IVD industry. With AdvaMed covering such a large spectrum of

companiesmanufacturers of everything from stents to orthopedics

and wound care productsGarrett sees AdvaMed Dx as a way for IVD

companies to have a strong voice on issues and perspectives that are

unique to their industry. Its our expectation that the positions and is-

sues 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 Ad-

vaMed, 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 anyfurther 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 leader-

ship 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 totake 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 hes been encouraged by the level of enthusiasm from the

major diagnostics companies. We expect AdvaMed Dx to be an impor-

tant part of our industry in the future, he said.



While certain segments of the POCTmarket have expanded rapidly, such asrapid testing for the 2009 H1N1 virus,POCT certainly cannot substitute for allcore lab tests. Point-of-care has to balancea lot of things: turnaround, precision andaccuracy, and cost-per-test, and I dont seethe technology there yet for point of care totake over as much as people are predicting,said Beckman Coulters Zakowski. The in-creased cost of POCT has to be trumped bysome workflow advantage within the site

of care, or it cant be successful. Essentially,the test must help the hospital move the pa-tient forward in a meaningful way, such asblood gas in intensive care units or coagu-lation tests in emergency departments andoperating rooms. These kinds of tests allowclinicians to test and treat more efficiently,and have moved forward at an ambitiousrate, Zakowski said.

However, a manufacturer must studythe cycle of care attentively if it wants tomake the extra dollar or so for a POC testto be worth it. For instance, with bloodgas testing, clinicians might actually needblood gas, basic metabolic panel and lactate

results before theyre comfortable movingthe patient forward, explained Zakowski.So just offering the quick blood gas will,in some situations, do nothing for clini-cians because they still have to wait for theother tests from the main lab. It can actu-ally make the workflow more complicatedbecause clinicians have to look for answersfrom two separate places. I think POCTis a promising piece of the market, but ithas some very particular demands, hesaid. And its not really taking from mainlab volumes, but mostly complementary,in fact. So its an opportunity more than athreat for the main lab.

POCT is also a hot area for startupcompanies with many of them develop-ing POCT multiplexing platforms that usedisposable cartridgessome in hematol-ogy, and even in the molecular area, notedthe consultants from EAC. Hughes andFarber indicated that technology has byno means peaked for POCT, consideringall the promising innovations at these newcompanies.

According to Abbotts Chaitoff, the abil-ity of manufacturers to pull out all the stopsin POCT technology is what will make thedifference in the marketplace of the future.Whether we are talking about POCT, mo-

lecular, or traditional core lab diagnostics,the key is that advanced technologymicrofluidics, nanotechnology, advancedchemistries, biologic breakthroughs, andinformation sciencesall are going to haveto converge more and more to achieve goalsaround productivity, outcomes, and physi-cian and patient satisfaction, he said. Andyes, reduced overall healthcare costs.

Still Betting on Pharmacogenomics

Part of the surprisingly positive outlookfor the overall IVD market draws from theconsensus among laboratorians and IVDcompanies that in the final analysis, diag-

nostics can improve both healthcare qual-ity and cost-effectiveness. Of course, this isin spite of the way payment policy handeddown from Congress and the Center forMedicare and Medicaid Services (CMS)rarely seems to recognize this fact. Formany, pharmacogenomics symbolizes theway in which advances in diagnostics canhave a big impact on the future of medi-

cine. And manufacturers want to be surethey get a piece of the action when the fieldmatures.

While the 20th Century witnessedan unprecedented growth in the develop-ment of medications and therapies, thiscentury will witness a similar explosion inthe development of diagnostic tests, saidAbbotts Chaitoff. Human blood is over-flowing with molecules and proteins thateach have a story to tell. Until recently, wehad very limited knowledge of what these

molecules and proteins did. Advanced di-agnostics will lead to a wider recognition ofthe value of the lab and diagnostics to solvemany of our pressing healthcare needsfrom optimizing patient care to reduce thefinancial burden on the healthcare system.

Ironically, the federal governmentsdrive to eliminate waste and reduce the

amount of reimbursement will turn intoan advantage for pharmacogenomic testsif manufacturers play their cards right, saidErnst & Youngs Ramko. The challenge willbe to prove to payers that advanced testsreally do make a difference in care, reducecosts, and therefore deserve reimburse-ment themselves. With big pharma devel-oping fewer small-molecule type drugs andmoving to more expensive biologics, therewill be an emphasis on making sure that atreatment will really work, he said. Clear-

ly the push is going to be to reduce costs, tonot pay for things that are unnecessary. Asthe move to reduce cost is more and moreacute, suppliers of treatments are going toneed pharmacogenomics to prove how atherapy can work for certain targeted indi-viduals instead of offering it to everybodyto see what works.

Pharmaceutical companies will be us-ing pharmacogenomics in the researchand development phase of drugs and asa tool to show the government and otherpayers why they should get reimburse-ment, Ramko emphasized. And just likemore mature sectors of the IVD market,manufacturers will have to put a focusedeffort into proving the value of a new testfor this purpose.

Although widespread use of pharma-cogenomic tests has not yet arrived, manu-

facturers want to make sure that theyre notleft out when the time comes, said EACsFarber. People are really starting to cometo grips with the reality of companion di-agnostics, and were now getting very seri-ous inquiries about where the market is go-ing and how a company can position itselfto do something about it. CLN
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abrupt loss of kidney function that leads tofluid retention, accumulation of metabolicwaste products, and dysregulation of extra-cellular volume and electrolytes. Commoncauses of AKI range from decreased renalperfusion and contrast-induced neph-ropathy to sepsis and nephrotoxicity frommedications such as aminoglycoside anti-

biotics and non-steroidal anti-inflamma-tory drugs. AKI now is the preferred termover acute renal failure, to emphasize therange of AKI disease from early injury toprogressive loss of function requiring renalreplacement therapy.

Two classification systems for the con-dition proposed in recent years are gainingacceptance. Both rely on changes in serumcreatinine levels and urine output. TheAcute Kidney Injury Network (AKIN) de-fined AKI as an reduction in kidney func-tion within 48 hours, involving an absoluteincrease in serum creatinine of 0.3 mg/dL,a percentage increase of 50% or 1.5 times

above baseline, or documented oliguria ofless than 0.5 ml/Kg per hour for more than 6hours. Meanwhile, the Acute Dialysis QualityInitiative issued the Risk, Injury, Failure, Lossand End-stage (RIFLE) criteria, which usegraded increases in glomerular filtration ratebased on serum creatinine levels and weight-dependent urine output parameters.

Nationally, AKI accounts for at least3%4% of all hospitalizations and may bea contributing factor in more than one-third of all admissions, at a cost of about$10 billion annually. At the same time,the incidence of AKI in the community isrising, with an estimated rate of 500 per

100,000 population in 2002, up from ap-proximately 61 per 100,000 population in1988. Adding to the magnitude of thesefigures, 20%30% of critically ill patientsdevelop AKI, and depending on the patientpopulation, mortality following an episodeof AKI is estimated to be between 40% and60%. Validation of both the AKIN andRIFLE systems has underscored the impor-tant effects of small declines in glomerularfiltration rate on the overall outcome ofcritically ill patients, according to Okusa.Even the least severe categories, R inRIFLE or AKIN stage I, have been associ-ated with a mortality rate of approximately

30 percent, he indicated.In addition, recent research has changed

the thinking about the natural course ofAKI. Previously kidney function was gen-

erally thought to completely return to nor-mal, but information now suggests that thelong-term course for a significant numberof patients with AKI is high-stage chronickidney disease, noted Paul Kimmel, MD,senior advisor in the Division of Kidney,Urologic and Hematologic Diseases at theNational Institute of Diabetes and Digestiveand Kidney Diseases (NIDDK). AKI seems

to go on to progressive injury, and the ideanow is that there is a spectrum of functionalkidney responses after AKI. Kimmel also isproject scientist for the NIDDK-funded As-sessment, Serial Evaluation, and SubsequentSequelae in Acute Kidney Injury (ASSESS-AKI) research initiative.

A Lackluster Gold Standard

Even as research is elucidating the pathol-ogy of and outcomes associated with AKI,treatment advances have been hamperedby lack of sensitive and specific biomarkersfor the condition. Although it is still con-sidered the gold standard, serum creatinine

is far from an ideal parameter, accordingto Norbert Lameire, MD, emeritus profes-sor of medicine at the University of Gent,Belgium, and co-chair of the Kidney Dis-ease: Improving Global Outcomes clini-cal practice guidelines on AKI. In AKI ittakes at least 24 hours, and in many cases,48 hours, before you see a significant in-crease in serum creatinine. So you lose thiscrucial, lets say 36 hours, in which a lot ofinjury has gone on before you see it in yourserum creatinine. As much as 50% of kid-ney function can be lost by the time serumcreatinine levels reach abnormal levels.Serum creatinine also is affected by non-

renal factors, such as protein intake, musclemass, age, and sex, and it is not sensitive tokidney insults that do not affect filtration.Until recently, these biological varianceswere compounded by analytical challenges,but over the past several years considerableindustry-wide effort has gone into stan-dardization and commutability of serumcreatinine measurements.

All-in-all, these shortcomings have hadthe compound effect of not only holdingback treatment advances but also delay-ing anti-AKI drug development. A seriesof summits in 2004, sponsored by the ASNand with participation from NIDDK, FDA,

and other professional associations, high-lighted that reliance on serum creatininewas stifling therapeutic progress, accord-ing to Chirag Parikh, MD, PhD, associateprofessor of medicine at Yale UniversitySchool of Medicine. People realized wednot made any progress in terms of patientcare and morbidity and mortality of AKI.Serum creatinine was not only hinderingdiagnosis and treatment, but it was weaken-ing the drug development process. Earlier,more sensitive biomarkers would enablephysicians to fine-tune the basics of AKItreatmentblood pressure managementalong with reperfusion and vasopression

therapyand enable them to start dialysisearlier when needed. Above all, better bio-markers ultimately would lead to develop-ment of drugs that would halt quickly theprogression of AKI.

Unprecedented Enthusiasm

Since the 2004 summits, research has accel-erated rapidly, to the point that some pro-

posed biomarkers are tantalizingly closeto being implemented in clinical practice.Theres now unprecedented enthusiasmin nephrology for early AKI biomarker de-tection research, observed Parikh. There

is a pipeline of development full of numer-ous possibilities and it is very likely a testor tests will come from that pipeline thatare good enough to replace the currentparadigm of care. A review he conductedin 2008 identified 21 serum and urinebiomarkers of AKI that had utility in thedifferential diagnosis, early detection and/or prognosis of the condition (Kidney Int2008;73:100816). These markers also havebeen associated with injury to specific seg-ments of the kidney nephron, such as theproximal and distal tubules, Loop of Henle,and collecting ducts, placing them in therealm of structural indicators of injury

in contrast to serum creatinines role as afunctional parameter.

Of the many potential markers, neutro-phil gelatinase-associated lipocalin (NGAL)is at the top of many researchers lists. Alsoknown as lipocalin-2 or siderocalin, NGALis a protein in neutrophils that rises within24 hours after kidney injury. Arguablythe most studied emerging marker of AKI,

NGAL has been investigated across a broadrange of clinical settings, including post-car-diac surgery, critical and emergency care, aswell as in adult and pediatric populations. Arecent meta-analysis of 19 studies involving

more than 2,500 patients found that the areaunder the curve/receiver operating char-acteristic of NGAL to predict AKI overallwas 0.815, 0.775 in cardiac surgery patients,0.728 in critically ill patients, and 0.894 fol-lowing contrast infusion, respectively (AmJ Kidney Dis 2009;54:101224). NGALshowed better predictive ability in childrenthan adults, and it appeared to be useful inpredicting renal replacement therapy and,to some extent, in-hospital mortality. Ouranalysis found that NGAL appears to havediagnostic value for early AKI and prognos-tic value for renal replacement therapy andmortality, both overall and across a range of

subgroups, said lead author Michael Haase,MD, assistant professor of nephrology andintensive care medicine at Charit-Universi-ty Medicine Berlin in Germany.

The Need for More Data

As promising as this analysis appeared to be,it highlighted the challenge facing imple-mentation of all the AKI biomarkers under

Serum Creatinine Inadequate MeasureAcute Kidney Injury, from page 1

For Further InformationAcute Kidney Injury Network:report of an initiative to improveoutcomes in acute kidney injury,http://ccforum.com/content/11/2/R31

Acute renal failuredefinition,outcome measures, animalmodels, fluid therapy and infor-

mation technology needs: theSecond International ConsensusConference of the Acute DialysisQuality Initiative (ADQI) Group,http://ccforum.com/content/8/4/R204

Kidney Disease: ImprovingGlobal Outcomes,www.kdigo.org

Tracking the Courseof Acute Kidney Injury

Landmark Study Will Evaluate New MarkersAlthough numerous potential biomarkers for acute kidney injury (AKI)have been identified and investigatedmany with favorable perfor-mance profilesthe candidate markers need further evaluation inlarger, more diverse populations for longer periods of time in order toachieve breakthroughs in AKI care. A major National Institute of Diabe-tes and Digestive and Kidney Diseases (NIDDK) initiative seeks to do justthat.

Assessment, Serial Evaluation, and Subsequent Sequelae in AcuteKidney Injury (ASSESS-AKI) is a landmark study that will follow for amean of 3 years a diverse population of 1,200 patients in a range ofclinical settings at three participating centers. ASSESS-AKI has twoprimary goals: determining whether hospitalized patients with anepisode of AKI are at greater risk of developing chronic kidney diseasethan patients without AKI, after adjusting for pre-existing levels ofkidney function and potential confounders; and determining whetherthese AKI patients are at higher risk for death, cardiovascular and otheradverse events after hospitalization than control subjects.

Our purpose is two-fold. One is to provide more information aboutthe natural history of AKI, particularly acute tubular necrosis in hospital-ized patients, explained ASSESS-AKI project scientist Paul Kimmel, MD,who also is senior advisor in the Division of Kidney, Urologic and Hema-

tologic Diseases at NIDDK. The other is to develop our understandingof how biomarkers can help in predicting outcomes, specifically long-term kidney response in patients who develop AKI.

ASSESS-AKI began enrolling patients in December 2009; outcomesfrom the trial are expected by the end of 2013. Evaluating currentlyused and novel biomarkers will be a key aspect of the study. At least fiveunique blood and urine samples will be collected over the course of 3years from 600 patients with AKI and 600 matched controls. A minimumof 16 novel urine and 10 novel serum biomarkers will be measured, inaddition to standard tests such as urine and serum creatinine, bloodurea nitrogen, urine and blood albumin, calcium, and glucose, amongothers. I ts quite likely, because well have enough patients, statisticalpower, and tests, that well be able to find any relationships betweennew biochemical assays and long-term outcomes that may exist, saidKimmel.

ASSESS-AKIs precise sample collection, handling and storageprotocols also are expected to advance the AKI evidence base, ac-cording to Kimmel. One of the things were trying to do is to put ourmeasurements into a clinical context. So if we learn that urine has to behandled in a certain way or we lose certain markers, but find that theresa six hour delay until its processed in a standardized manner in all thestudys different clinical sites, that will be very important. The utility ofsomething that has to be collected under extremely specified condi-tions will be less generalizable.
http://ccforum.com/content/11/2/R31http://ccforum.com/content/11/2/R31http://ccforum.com/content/8/4/R204http://ccforum.com/content/8/4/R204http://www.kdigo.org/http://www.kdigo.org/http://ccforum.com/content/8/4/R204http://ccforum.com/content/8/4/R204http://ccforum.com/content/11/2/R31http://ccforum.com/content/11/2/R31



investigation. Most importantly, there hasyet to be a prospective validation study ina large number of patients with differentcauses of AKI. The majority of studies havebeen in small populations or single centersexamining AKI in one setting or clinicalcircumstance, such as post-cardiac surgeryor in critically ill children. In addition, withNGAL and various other proposed bio-

markers, a variety of test platforms havebeen used with different protocols and ref-erence ranges. For instance, the majority ofstudies identified in Haases meta-analysisused CLIA-waived ELISAs, with NGALreference ranges for the non-AKI controlpopulations varying from



Despite being well recognized as acomplication of pregnancy, many un-knowns still surround prediction, di-agnosis, and pathophysiology of preec-lampsia, earning it the common name,disease of theories. Efforts to lessen therisks associated with preeclampsia havebeen focused on accurate and earlier di-

agnosis of the disorder. New biomarkersfor predicting and possibly preventing

preeclampsia promise to give the labo-ratory a major role in the care of at-riskpregnant women. Here we describe thecurrent understanding of the etiologyof preeclampsia, the labs current rolein monitoring at-risk women, as well ashow new biomarkers on the horizon maylead to greater involvement of the lab inearlier prediction of the condition.

Risk Factors for PreeclampsiaEpidemiological and clinical risk factors forpreeclampsia are classified as maternal, pa-ternal, and/or pregnancy-specific (Table 1,p. 9). One hypothesis concerning the etiol-ogy of preeclampsia is that it is an autoim-mune disorder and may reflect the imma-turity of the maternal immune system to

properly respond to the pregnancy. Thishypothesis originates from the fact that

the frequency of preeclampsia is higher innulliparous women, women who conceivewith assisted reproductive techniques, andwomen with autoimmune conditions.

In addition, pre-existing metabolic,renal, or vascular conditions increase therisk of preeclampsia due to the physi-ological stress of pregnancy combinedwith widespread endothelial dysfunction.

Obese (BMI30 Kg/m2) females are at veryhigh risk for preeclampsia compared tolean women (odds ratio = 3.3), as well aswomen who have hypercholesterolemia orhypertriglyceridemia. On the other hand,smoking actually decreases a womans riskof preeclampsia.

Use of low-dose aspirin in women with

these risk factors has been shown to slightlyreduce the risk of preeclampsia (OR 0.86,95% CI: 0.760.96) and perinatal mortal-ity, but it failed to reduce placental abrup-tion or delivery of low-birth-weight babies(1). Researchers have also studied vita-mins C and E and calcium supplements inboth low- and high-risk populations butfound no evidence that these nutritionalsupplements reduced the prevalence ofpreeclampsia, hypertension, or eclamp-sia. Furthermore, preventive preeclampsiatrials so far have produced disappointingresults, perhaps due to an overall lack ofunderstanding of the causal mechanisms

of preeclampsia.

Pathophysiology of Preeclampsia

Current concepts and theories of thepathophysiology of preeclampsia revolvearound the common theme of endothe-lial cell dysfunction, primarily placental inorigin, but extending to other organs suchas the brain, liver, and kidneys. This long-standing hypothesis focuses on placentalimplantation and trophoblast invasion andoriginated after observations that deliveryof the placenta quickly reversed the clini-cal manifestations of preeclampsia and ec-lampsia in a majority of patients. Immune

maladaptation between the mother and fe-tus is also likely a factor in the developmentof preeclampsia, but the exact mechanismsare still unknown.

In normal pregnancy, the maternal-fetalinterface and blood flow are established veryearly after conception. Proper placental im-plantation allows for adequate circulationbetween the mother and fetus and occurs

PreeclampsiaPrediction, Diagnosis, and Management

Beyond Proteinuria and HypertensionBYDARCIR. BLOCK, PHD,ANDAMYK. SAENGER, PHD

Preeclampsia is a multisystem disorder of pregnancy characterized by the presence of hypertension

and proteinuria after 20 weeks gestation. While estimated to affect only 3%5% of all pregnancies

in the U.S., the disorder is responsible for 15% of premature deliveries and up to 18% of maternal

deaths. In fact, complications from hypertension in pregnancy are the third leading cause of mater-

nal death, surpassed only by embolism and hemorrhage. Other risks associated with preeclampsia

include placental abruption, liver or renal failure, disseminated intravascular coagulopathy, cardiovascular com-

plications, and seizures or other neurological manifestations (eclampsia).

The incidence of preterm birth is also higher in preeclamptic women, primarily because obstetricians attempt

to minimize the risks to both the mother and fetus by delivering the fetus early. However, preterm infants are

at risk of complications as well. They have a greater probability of developing respiratory distress syndrome, in-

traventricular hemorrhage, cerebral palsy, and other neurological and developmental delays. In women whose

preeclampsia is caused by placental anomalies, severe intrauterine fetal growth restriction may occur, leading to

higher prevalence of intrauterine asphyxia and placental abruption.

CLNS

IMPROVING

HEALTHCARE

THROUGH

LABORATORY

MEDICINE

SERIES



when the placenta cytotrophoblast cellsinvade the maternal spiral arteries, causingthem to lose their smooth muscle and en-abling expansion of vascular capacity andangiogenesis. In preeclamptic patients theimplantation of the placenta may be dys-functional, such that the spiral arteries are

poorly remodeled, resulting in inadequatecirculation between the placenta and theuterus and ultimately a shallow placentalimplantation. This lack of perfusion orischemia is thought to induce a majority ofthe endothelial dysfunction and lead to de-velopment of widespread organ alterationsand detectable alterations in the cardio-re-nal system. Therefore, even though the lo-calized endothelial changes originate fromthe placenta, the consequences of decreasedperfusion extend to all other organs. Bloodflow is further compromised by activationof the coagulation cascade and formationof microthrombi.

The severity of symptoms has also pro-vided clues as to the pathophysiology of thedisorder. Preeclampsia diagnosed early inpregnancy, before 34 weeks, has a higherprobability of placental abnormalities andrepresents the most severe cases of preec-lampsia and intrauterine growth restric-tions in the baby. However, a majority ofpreeclampsia cases are late onset, diagnosedafter 34 weeks, and notably lack placentalanomalies and major adverse complica-tions.

Diagnosis and Laboratory Testing

Obstetricians typically diagnose preec-

lampsia after 20 weeks gestation. Maternalpresentation of new onset hypertension,proteinuria, and often edema trigger the di-agnosis. Severe preeclampsia is recognizedby a greater magnitude of increased bloodpressure and a greater degree of proteinu-ria. Other clinical manifestations of severepreeclampsia include oliguria, cerebral orvisual disturbances, and pulmonary edema.While the presence of hypertension is oftenthe first sign of preeclampsia, hypertensionalone does not define the disorder. Thepathogenic evolution and progression ofpreeclampsia likely originates shortly afterconception, and hypertension becomes ap-

parent later in the pregnancy.The American College of Obstetricians

and Gynecologists recognizes four majorclassifications of hypertension-related dis-orders in pregnancy (2). These disordersinclude chronic hypertension, preeclamp-sia/eclampsia, preeclampsia superimposedon chronic hypertension, and gestationalhypertension (Figure 1).

Chronic hypertension is unrelated to thepregnancy itself and is diagnosed if there isa documented pre-existing condition priorto 20 weeks gestation or if the hyperten-sion persists at 12 weeks postpartum. Pre-eclampsia is defined as hypertension and

proteinuria after 20 weeks gestation, whileeclampsia is a severe progression and com-plication of preeclampsia and is indicatedby new onset of seizures in previous pre-eclamptic women. Full eclampsia is rela-tively rare and estimated to occur in only1% of preeclamptic patients.

Preeclampsia superimposed on chronichypertension is characterized by new-onset

proteinuria or by a marked increase in pro-tein concentration if already present, anacute increase in hypertension, or develop-ment of HELLP (hemolysis, elevated liverenzymes, low platelet count) syndrome.Women may also have gestational hyper-tension. This condition is diagnosed whenthere is documented maternal hyperten-sion without the presence of proteinuria,and the hypertension ceases by 12 weekspostpartum. However, approximately 25%of women with gestational hypertension

develop proteinuria and progress to preec-lampsia.

Currently, diagnosis and therapeuticmonitoring of the progression of preec-lampsia does not involve specific or sen-sitive blood biomarkers (Table 2, p. 10).Therefore, involvement of the laboratory inthe diagnosis has been minimal. However,the search for novel diagnostic markers forpreeclampsia is an active focus of research,and there are several promising new bio-markers on the horizon that have the po-tential to give the lab a greater role.

Emerging Biomarkers for Preeclampsia

Research has shown that endothelialdysfunction produces an imbalance of pro-and anti-angiogenic factors, making fac-tors involved with the angiogenesis processof placental formation and implantationgood candidate biomarkers for preeclamp-sia. Several circulating factors have beenidentified that are involved in this process.Pro-angiogenic factors include vascular

Table 1

Preeclampsia Risk FactorsMaternal Considerations

Inherent l Age < 20 or 3540 years

l Nulliparity l Black race

l Prior or family history of PE or cardiovascular disease l Woman born small for gestational age

Medical conditions

l Obesity l Chronic hypertension l Chronic renal disease l Diabetes mellitus (insulin resistance, type 1, and gestational) l Antiphospholipid antibody syndrome l Connective tissue diseases lThrombophilia l Stress

Pregnancy specific l Multiple gestation l Oocyte donation l Urinary tract infection l Congenital conditions affecting the fetus

Hydatidiform mole Hydrops fetalis Structural anomalies

Paternal ConsiderationsLimited sperm exposure

l Barrier contraception l First-time father l Donor insemination

Partner who fathered a preeclamptic pregnancy in another woman

Adapted from reference 2 and Dekker G, Sibai B. Primary, secondary, and tertiaryprevention of preeclampsia. Lancet 2001;357:20915.

Figure 1

Classification of Preeclampsiaand Pregnancy Related Hypertension

Adapted from reference 2 and Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure inPregnancy. Am J Obstet Gynecol 2000;183:S122.



endothelial growth factor (VEGF) andplacental growth factor (PlGF), while anti-angiogenic factors include soluble fms-liketyrosine kinase 1 receptor (sFlt-1) and sol-uble endoglin (sEng).

Expressed by the placenta, VEGF andPlGF promote angiogensis by interactingwith the VEGF receptor. PlGF serum con-centrations in pregnancy increase signifi-cantly and to a much greater extent thanVEGF levels. Several studies have shownthat PlGF and VEGF concentrations both

decrease prior to the onset of clinical preec-lampsia symptoms, although the magni-tude of difference from normal pregnancyvalues is greater for PlGF than VEGF. Inparticular, researchers have found thatwomen who later developed preeclampsiahad reductions in serum PlGF in the sec-ond trimester.

In addition to placental growth factorsrecruited for the purposes of angiogen-esis and placental implantation, researchershave identified proteins that counteract theeffect of PlGF and VEGF. sFlt-1, also knownas soluble VEGF receptor 1, circulates in theblood and is capable of binding VEGF and

PlGF to further inhibit receptor bindingand angiogenic effects. Studies have shownthat sFlt-1 is elevated in women with preec-lampsia compared to controls, correlates todisease severity, and subsequently decreasesfollowing delivery (3, 4). Moreover, the ra-tio of sFlt-1 to PlGF is useful as an indexof anti-angiogenic activity, reflecting bothincreased sFlt-1 and decreased PlGF inwomen who develop preeclampsia.

Studies have also indicated that thesFlt-1:PlGF ratio predicts preeclampsia upto 5 weeks earlier than clinical diagnosismade with current markers or either pro-tein alone. Interestingly, sFlt-1 given exog-

enously in pregnant rats triggered devel-opment of hypertension, proteinuria, andglomeruloendotheliosis (5).

Another factor involved in angiogen-esis of the placenta is soluble endoglin(sEng). This protein is a circulating formof endoglin that is expressed on the vascu-lar endothelium and trophoblast cells andfunctions as a modulator of transform-ing growth factor (TGF-)signaling. sEngcompetes directly with TGF-and acts as anegative regulator of angiogenesis. Similarto sFlt-1, soluble endoglin concentrationscorrelate to the occurrence and severityof preeclampsia and resolve following de-

livery. Furthermore, sEng levels have beenshown to be significantly higher 3 monthsprior to the development of proteinuria orhypertension, whereas the sFlt1:PlGF ratioincreases closer to disease onset (3, 4).

Pregnancies in which there is intrauter-ine growth restriction unrelated to preec-lampsia also demonstrate elevated levelsof sEng, suggesting this marker may notbe specific for preeclampsia but rather fora dysfunctional placenta. Animal modelstudies demonstrate that induction of thehepatic and renal complications that occurwith HELLP syndrome transpire after ad-ministration of sEng and sFlt-1, suggesting

that the two proteins may have a synergisticeffect responsible for the more severe casesof PE (6).

Although PlGF, VEGF, sFlt-1, and sEngall appear to be important in the pathogen-esis of preeclampsia, they do not have suffi-ciently high positive-predictive value whenused alone. Based on the overall findings,it seems likely that a combination of these

markers will improve their utility as predic-tors or preeclampsia.

There are several other biomarkers thatalso show promise in the prediction tomanagement of preeclampsia. These in-clude: placental protein 13 (PP-13); asym-metric dimethylarginine (ADMA); cell-freeDNA; pregnancy-associated plasma proteinA (PAPP-A); autoantibodies against the an-giotensin II type 1 (AT1) receptor; inhibinA; and activin A. Larger longitudinal, case-controlled trials are needed to validate the

clinical and analytical characteristics ofthese markers.

Treatment of Preeclampsia

Delivery of the baby is the only cure forpreeclampsia. Prenatal treatment optionsare limited due to the potential risks tothe fetus; therefore, patients with preec-lampsia are simply monitored for signsand symptoms of distress. Obstetriciansmonitor blood pressure and lab tests resultsin women with mild preeclampsia twiceweekly to indicate progression to HELLPor eclampsia with liver and kidney involve-ment. Women with severe preeclampsia are

put on mandatory bed rest and monitoredin a similar manner to prevent seizures andlower their blood pressure.

Magnesium sulfate has been used todecrease the incidence of seizures and mayalso have the added benefit of decreasingplacental abruption. Patients receiving thistherapy must be monitored closely for mag-nesium toxicity, especially for decreasedliver and kidney function. Antihypertensivedrugs may also be used for the treatmentof acute maternal symptoms, and the fetusmay be given corticosteroids to assist withlung maturity as a precaution for impend-ing delivery.

Other treatment options are also beingexplored. Administrating a VEGF variantto an sFlt-1 overexpressing rat model wasfound to reverse the preeclamptic pheno-type without apparent harm to the fetus(7). This and other ongoing studies areaimed at elucidating the etiology of disease,as well as restoring angiogenic balance.

Beyond Postpartum

Although preeclampsia is a disorder ofpregnancy, the higher relative concentra-tions of anti-angiogenic factors are thoughtto trigger widespread vascular endothe-lial cell injuries, as well as induce an altered

cardiovascular state during the affectedpregnancy and beyond. The risk factors forcardiovascular disease and preeclampsiaare remarkably similar and include: obesity,hypertension, hyperglycemia, insulin resis-tance, diabetes, and dyslipidemia (Table 1,p. 9).

Several epidemiological studies haveprovided convincing evidence that cardio-vascular risk is increased in women with ahistory of preeclampsia compared with nor-mal control subjects, particularly if they de-liver a preterm, low-birth weight baby. Onecontributing factor may be the occurrenceof microalbuminuria 35 years postpar-

tum, which occurs in up to 50% of womenwith a history of preeclampsia compared towomen with no history of the disorder. It isuncertain how long this condition persists,but there is a significant link to increasedcardiovascular risk and microalbuminuriain menopausal women (8).

Authors of a recent meta-analysis alsoreported several associations between pre-

eclampsia and cardiovascular morbidityand mortality. In women diagnosed withpreeclampsia, there is approximately afour-fold risk of future hypertension andan approximate two-fold risk of ischemicheart disease, venous thromboembolism,and stroke (9). In addition, if preeclampsiais diagnosed in a subsequent pregnancy, therisk of future hypertension and cardiovas-

cular events increases even further.

On the Horizon: Preeclampsia Biomarkers

Preeclampsia is clearly a complex disorderthat involves a delicate balance betweenthe maternal immune system, fetus, andplacenta. Readily accessible screening testsfor preeclampsia would ideally reduce theincidence of maternal and neonatal com-plications.

Several preeclampsia biomarkers are indevelopment and being evaluated on auto-mated immunoassay platforms. If thesemarkers prove to have adequate sensitivityand positive-predictive value in screening

for preeclampsia, labs will have the op-portunity to help improve the quality ofcare for outcomes of obstetrical patients.With new biomarkers, earlier prediction ofpreeclampsia in high-risk pregnancies willallow obstetricians to treat women earlierand hopefully improve outcomes for boththe mother and the fetus. CLN

REFERENCES

1. Coomarasamy A, Honest H, Papaioan-nou S, Gee H, et al. Aspirin for preventionof preeclampsia in women with historicalrisk factors: a systematic review. Obstet Gy-necol 2003;101:131932.

2. Gilstrap L, Ramin S. ACOG Committeeon Practice Bulletins: Diagnosis and man-agement of preeclampsia and eclampsia.ACOG Practice Bulletin Clinical Manage-ment Guidelines for Obstetrician-Gynecol-ogists 2002;33:19.

3. Carty DM, Delles C, Dominiczak AF. Nov-el biomarkers for predicting preeclampsia.

Trends Cardiovasc Med 2008;18:18694.

4. Levine RJ, Lam C, Qian C, Yu KF, et al.Soluble endoglin and other circulatingantiangiogenic factors in preeclampsia. NEngl J Med 2006;355:9921005.

5. Maynard SE, Min JY, Merchan J, LimKH, et al. Excess placental soluble fms-liketyrosine kinase 1 (sFlt1) may contribute toendothelial dysfunction, hypertension, and

proteinuria in preeclampsia. J Clin Invest2003;111:64958.

6. Venkatesha S, Toporsian M, Lam C, Ha-nai J, et al. Soluble endoglin contributes tothe pathogenesis of preeclampsia. Nat Med2006;12:6429.

7. Steinberg G, Khankin EV, KarumanchiSA. Angiogenic factors and preeclampsia.Thromb Res 2009;123:S939.

8. Davison JM, Homuth V, JeyabalenA, Conrad KP, et al. New aspects in thepathophysiology of preeclampsia. J Am SocNephrol 2004;15:24408.

9. Bellamy L, Casas J, Hingorani AD, Wil-

liams DJ. Pre-eclampsia and risk of car-diovascular disease and cancer in later life:systematic review and meta-analysis. BMJ2007;335:97485.

Darci S. Block, PhD, is a

clinical chemistry fellow in

the Department of Labora-

tory Medicine and Pathology

at the Mayo Clinic, Rochester,

Minn. Email: [email protected].

Amy K. Saenger, PhD, is

the director of the Central

Clinical Laboratory andan assistant professor in the

Department of Laboratory

Medicine and Pathology at the Mayo Clinic,

Rochester, Minn. Email: saenger.amy@

mayo.edu.

Disclosure: Dr. Saenger has received grant/

research support from Roche.

Table 2

Laboratory Tests forPreeclampsia and Eclampsia

Assessment for High Risk of Developing PreeclampsiaGoal: Establish baseline levels early in pregnancy and monitor forprogression to HELLP or severe preeclampsia.

CBC l Hemoglobin l Hematocrit lPlatelet count

Urine protein (12 or 24 hour)

Serum creatinine

Serum uric acid

Diagnosis of HELLP Syndrome

Hemolysis lB ilirubin . . . . . . . . . . . . . . . . . . . . . . >1.2 mg/dL l Peripheral blood smear . . . . . . . abnormal l Lactate dehydrogenase . . . . . . . >600 U/L

Liver function testsl ALT & AST . . . . . . . . . . . . . . . . . . . . elevated

P latelet count . . . . . . . . . . . . . . . . . .



Expanding Role of the Clinical Lab in Infectious Disease Testing

QWhat are the best laboratory testsfor the diagnosis of sepsis and septicshock in emergency departments? What is

likelihood ratio of procalcitonin (PCT) in

septic syndrome triage in emergency de-

partments?

ASepsis is a complex disorder withconfusing clinical manifestations andconflicting signs and symptoms that canlead to increased morbidity and mortality.This is especially true for the ED clinicianwho must make rapid medical decisionsabout triage, diagnosis, and disposition to

the appropriate level of care for ED pa-tients with clinical signs and symptoms ofsepsis. Blood cultures have played a vitalrole in the differential diagnosis of sepsis,but PCT is an early biomarker of inflam-mation and bacterial sepsis and may beuseful as a rapid risk stratification tool inthe ED using negative and positive pred-icative values. However, laboratorians needto read and review the package insert fortheir particular PCT assay to determine thetests intended use. Considerations includehow the assay was cleared by the FDA andwhether it was cleared for use only in theICU setting or can be used in other set-

tings, such as the ED. The likelihood ratiomay contribute additional information,providing clinicians are familiar with howthis information can be used appropriatelyin their decision making process.

QOur ED physicians order influenza(A&B) and group A strep testing si-multaneously. Are the symptoms similar,

and is this a common ordering pattern?

ASymptoms of the flu and strep can bevery similar. Upper respiratory symp-toms, as well as rash, sore throat, and fevermay be common to both diseases, but theappearance of white pus in the adenoidarea is more typical of a strep infection.Since these symptoms can overlap quiteextensively it is appropriate, depending onthe presentation, that both screening tests

be performed.

QThere are a few high-risk HPV test-ing techniques. What are the advan-tages of each?

AAn HPV test is done to find a high-risk HPV infection in women, andthere are many types of HPV. High-risktypes of HPV (such as types 16, 18, 31, and45) cause changes in the cells of the cervixthat can be seen as abnormal findings on aPap test and have a higher risk of progress-ing to cancer. The first screening test fre-quently used is a hybrid capture DNA assaythat detects the HPV high-risk genotypes

16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59and 68. Some disadvantages of this assayinclude: false negatives due to inadequatecellularity; suboptimal vaginal specimensdue to limited clinical correlative data; and

cross-reactions with other genotypes. Thescreening test, if positive, may be a reflec-tion of the DNA genotyping test. As towhich particular techniques are better thananother, I think one needs to do side by sideevaluations and compare the data.

QHow much demand is there cur-rently for infectious diseases testingwith very rapid turnaround? How do yousee this changing over the next 5 years or

so, and what are the drivers of change that

may result in molecular testing in point-

of-care settings?

AThere is an increasing demand forrapid testing in all areas of the labo-ratory so clinicians can make importantrapid medical decisions regarding the tri-age, assessment, treatment, and dispositionof their patients to the appropriate level ofcare. This is particularly true in the hospitalsetting. In my opinion, we will see molecu-

lar testing at the point-of-care setting. Anexample might be molecular testing formethicillin-resistant Staphylococcus aureus.

QShould laboratorians help physiciansinterpret results? Currently, infec-tious disease experts are rarely knowl-

edgeable about rapid tests, their high

false-negative rates, or in HIV testing, false

positives if the timing of the reading is not

absolutely exact.

AThere is an expanding role for labo-ratorians, especially in assisting physi-cians with the interpretation of laboratory

tests. Laboratorians understand better thanphysicians the strengths and limitations ofthe tests performed in their laboratories,and physicians know better than laboratori-ans the physiological functions of the bodyand what a result means in the context of aparticular patient. I believe patients clearlybenefit when professionals from both are-nas collaborate on their behalf. On lab re-ports from our lab we provide additionalinformation such as sensitivity, specificity,NPV, PPV, and clinical conditions.

DisclaimerThe opinions and infor-

mation are the sole responsibility of the

presenter. AACC reviews the presentations

for overall appropriateness, but this shouldnot be construed as an endorsement by the

association or its employees of the opinions

and information offered here.

Supported in part by an education grant

from Siemens Healthcare Diagnostics.

A A C C S E X P E R T A C C E S S

Each month, AACCs Expert Access Live Online Program

features a different hot topic. Visit AACCs website for more

information and an archive of past presentations.

The following is an excerpt from the May 2009 presen-

tation by Denise L. Uetwiller-Geiger, PhD, MT(ASCP),

DLM(ASCP), director of laboratories and clinical research at

John T. Mather Hospital in Port Jefferson, N.Y.

The easiest decisionyoull make all year!

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Considered by many to be the best atdelivering hands-on, lab-focused informa-tion, Clinical Laboratory Newsis a must-read for everyone in the lab.

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Electronic Health RecordIncentive Taking Shape

The Centers for Medicare & MedicareServices (CMS) and the Office of theNational Coordinator for Health Informa-tion Technology (ONC) announced tworegulations that will help implement theelectronic health record (EHR) incentiveprograms enacted under the American Re-covery and Reinvestment Act of 2009 (Re-covery Act).

Part of the Obama administrations pushfor improved health information technolo-gy, physicians stand to gain from $44,000 to$64,000 each by demonstrating meaning-

ful use to CMS over a 5-year period, andhospitals may be able to get millions. Begin-ning in 2015, CMS will financially penalizeproviders who dont show meaningful useof EHRs. Incentive payments may begin assoon as October 2010 to eligible hospitals,

while incentive payments to other eligible

providers are slated for January 2011.The most anticipated and controversial

element of the program has been how CMSwould define meaningful use so that phy-sicians and hospitals will know that theirinvestments in EHRs will measure up andearn the rewards. The new regulations in-clude a proposed rule that finally definesthe central concept of meaningful use ofEHR technology. The other regulation, is-sued by ONC, sets initial standards, imple-mentation specifications, and certificationcriteria for EHR technology. Both regula-tions are open to public comment throughthe end of February.

It will not be easy to meet the defini-tion of meaningful use. The proposedrule requires that the physician or hospitaldemonstrate use of certified EHRs in a waythat improves quality, safety, and efficiencyof healthcare delivery; reduces healthcare

disparities; engages patients and families;improves care coordination; improvespopulation and public health; and ensuresadequate privacy and security protectionsfor personal health information.

The ONC regulation describes standardelectronic formats for clinical summariesand prescriptions; standard terms to de-

scribe clinical problems, procedures, labo-ratory tests, medications and allergies; andstandards for the secure transmission ofthis information using the Internet. It alsosets forth how an EHR can be certified.

Both agencies noted that regulationswill need to be updated over time as tech-nology advances. The CMS proposedrule and fact sheets are available from theCMS website, www.cms.hhs.gov/recovery/11_healthit.asp. ONCs interim final rulemay be viewed at http://healthit.hhs.gov/standardsandcertification.

HHS Outlines FirstHealth Security Strategy

Department of Health and Human Ser-vices (HHS)Secretary Kathleen Sebe-lius announced the national health securitystrategy, the nations first comprehensivestrategy focused on protecting peopleshealth during a large-scale emergency. Theplan sets priorities for government and non-government activities over the next 4 years.

Sebelius defined national health secu-rity as the nation and its people being pre-pared for, protected from, and resilient inthe face of health threats or incidents withpotentially negative health consequences,

such as bioterrorism and natural disasters.The plan provides a framework that aimsto build community resilience, strengthenand sustain health emergency response sys-tems, and fill current gaps.

The national health security strategy andthe accompanying interim implementationguide outline 10 broad objectives to achievehealth security: foster informed, empow-ered individuals and communities; developand maintain the workforce needed fornational health security; ensure situationalawareness so first responders are aware ofchanges in an emergency situation; fosterintegrated healthcare delivery systems that

can respond to a disaster of any size; en-sure timely and effective communications;promote an effective countermeasures en-terprise; ensure prevention or mitigation ofenvironmental and other emerging threatsto health; incorporate post-incident healthrecovery into planning and response; workwith cross-border and global partners to

enhance national, continental, and globalhealth security; and ensure that all systemsthat support national health security arebased upon the best available science, eval-uation, and quality improvement methods.

The strategy and implementation guideis available from the HHS website, www.hhs.gov/disasters.

ISO Developing eHealth Resource forDeveloping Countries

The International Standards Organiza-tion (ISO) announced that it will cre-ate a technical report to help emerging and

developing countries implement an inter-nationally harmonized health informaticssystem. The report will present informationin an accessible way to guide and facilitatethe adoption of international standards bycountries with limited resources and infra-structure. ISO will work on the document(ISO/TR 14639) in partnership with theWorld Health Organization.

The design, deployment, and main-tenance of a national eHealth infrastruc-ture can be a complex task, especially forthose new to the area, ISO noted in theannouncement. Scarce resources and ITexpertise make it difficult to put together

systems that are scalable, robust, and meet acountrys long-term needs. Most resource-limited countries have multiple verticalsystemsprograms geared to individualdiseases like HIVand lack a commonframework that could improve data collec-tion and reporting.

According to ISO, international stan-dards can help by providing globally har-monized specifications for the architecturalframework used to design eHealth systems,plan implementation, make build-or-buydecisions, and decide on acquisitions. Moreinformation is available from the ISO web-site, www.iso.org.

R E G U L A T O R Y

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The Assay You Can Trust...
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Clinical Laboratory News - Feb 2010