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FHS Researchers Develop Multi-Biomarker Panel to Predict Risk of Chronic Kidney Disease

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By Adam Bonislawski

A study examining more than 2,300 participants from the National Heart, Lung, and Blood Institute's Framingham Heart Study has identified three serum biomarkers that improve risk prediction for chronic kidney disease and microalbuminuria.

The results of the study, detailed in a paper published this week in the online edition of the Journal of the American Society of Nephrology, indicate that serum homocysteine and aldosterone are both significantly associated with CKD; and B-type natriuretic peptide, homocysteine, aldosterone are associated with MA.

In an email to ProteoMonitor, Caroline Fox, medical officer for the FHS, said the research served "dual purposes of identifying pathways and marker panels" that can be used both to predict patients at risk for CKD and MA and to develop a better understanding of the progression of the diseases.

CKD affects roughly 26 million adults in the United States – nearly 13 percent of the population – and is considered a risk factor for diseases including peripheral vascular disease, cardiovascular disease, and stroke. Nonetheless, Fox said, "risk prediction is a relatively new concept in the area of CKD." Serum creatinine – currently the primary biomarker for the disease – is a poor agent for detecting early kidney damage. And while hypertension and diabetes are known risk factors for the disease, these factors don't fully identify at-risk individuals.

The study compared the levels of seven biomarkers – C-reactive protein, aldosterone, renin, BNP, plasmiogen-activator inhibitor type 1, fibrinogen, and homocysteine – in serum taken from 2,345 FHS subjects. The baseline measurements were made on serum taken between 1995 and 1998 with follow-up done between 2005 and 2008. During this time, 213 of the 2,345 participants developed CKD and 186 developed MA.

Instead of screening broadly for differentially expressed proteins as is often done in discovery-phase biomarker work, the NHLBI researchers took a targeted approach to selecting the seven markers for evaluation, choosing them based on their association with pathways known to be important in cardiovascular disease and left ventricle remodeling. Because these diseases are linked to renal function, the researchers hypothesized that markers associated with them might show links to kidney disease, as well.

From the panel of seven markers, the researchers identified serum homocysteine, BNP, and aldosterone as adding information regarding CKD risk beyond traditional risk factors like hypertension and diabetes. Adding biomarker information for homocysteine and aldosterone increased the number of patients classified as high-risk candidates for CKD by seven percent. Likewise, an additional seven percent of patients were classified as high risk for MA upon adding biomarker information for those two makers and BNP.

The research, Fox noted, "should be considered preliminary, without clinical implications at this point." Additional trials replicating the results in clinical settings are needed. Also, because the patient sample was all white, it's unclear how generalizable the findings may be to other ethnicities.

Fox also said that the researchers will be expanding their work "to focus on broader biomarker panels," looking beyond the markers targeted for their ties to CVD-associated pathways.

The FHS was started in 1948 with the goal of observing subjects over time to better understand the development and progression of CVD. It launched with a cohort of 5,209 men and women from Framingham, Mass., between the ages of 30 and 62. Since then it has grown to include more than 9,000 participants spanning three generations who undergo examinations on a regular basis.

The subjects for the CKD biomarker work were drawn from the Framingham Offspring Study – an offshoot of the FHS that began in 1971 with the enrollment of 5,124 men and women. These participants have undergone examinations roughly every four years, and the data for the CKD study was taken from the participants' sixth and eight quadrennial examinations.

The CKD study is another example of the FHS's move in recent years to include more biomarker and proteomics research. In November 2006 the study put out a solicitation for commercial and/or academic groups interested in using FHS blood samples for biomarker discovery work.

In March 2009, the study signed an agreement with the biotech firm BG Medicine aimed at discovering biomarkers, including protein biomarkers, associated with heart disease (PM 08/06/2010).

The five-year agreement calls for Sigma to create antibodies that can validate roughly 180 biomarkers associated with CVD, and to develop and run the validation assays on a multiplex platform in its St. Louis laboratory.

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