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For CKD, work is on to refine and find biomarkers

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Karen Lusky

July 2015—Getting the upper hand on chronic kidney disease requires taking maximum advantageof existing CKD biomarker capabilities. It also means discovering new markers, though the trick is finding those that can expand treatment options. Some believe fibroblast growth factor-23 has the potential to fit that bill, with one researcher calling it “among the most exciting new targets in chronic kidney disease.”

Urine albumin, creatinine, and newcomer cystatin C have their strong points. Each has its pitfalls, too, which stem from the nature of the biomarker itself, testing accuracy issues, or sometimes knowledge gaps about how to use or interpret a test result.

“Laboratory professionals should be aware that both clinicians and patients may look at these [test] results as absolute without understanding the variables that may affect measurements,” says Andrew Narva, MD, director of the National Kidney Disease Education Program at the National Institutes of Health, who is often on the stump educating clinicians and sometimes laboratory professionals about laboratory assessment of chronic kidney disease.

“About half of the people identified as having CKD in the U.S. have that diagnosis only on the basis of increased urine albumin,” Dr. Narva says. “You can have albuminuria or decreased glomerular filtration rate, or both.”

Dr. Bachmann

Dr. Bachmann

Urine albumin is the best biomarker for the more common causes of kidney damage: diabetes, hypertension, and cardiovascular risk factors, says W. Greg Miller, PhD, professor of pathology at Virginia Commonwealth University Medical Center, chair of the NKDEP Laboratory Working Group, and member of the CAP’s Accuracy-Based Testing Committee and of the International Standards Organization Technical Committee 212 Working Group 2 on Clinical Laboratory Reference Measurement Procedures and Materials. “A lot of different studies over time have shown very clearly that the albumin/creatinine ratio in the first morning void is very nearly identical to the 24-hour urine albumin excretion rate,” Dr. Miller says. The albumin/creatinine ratio, or ACR, “compensates pretty nicely for hydration,” he adds. The standard cutoff is 30 mg per gram of creatinine.

Misunderstandings about the ACR can sidetrack clinical care, however. In a talk at last year’s AACC annual meeting, Dr. Narva reported that he frequently gets questions from clinicians such as, “‘We did the microalbumin test. It came back 5,726. What do I do now? Do I get a 24-hour urine?’ I say, ‘No, that patient is in big trouble. That patient has about 6 grams of urinary albumin per day.’”

“The other issue,” Dr. Narva said, “is the multiple names that are given to these tests, and many clinicians think that if you have a little bit of kidney disease, you have the little albumins, the microalbumins, and then if you have bad kidney disease, the big albumins come out. They don’t understand that it’s all albumin and that’s a continuous risk factor.”

Dr. Miller

Dr. Miller

Urine albumin isn’t standardized, which can affect diagnosis and follow-up, especially if clinicians aren’t aware of it. Dr. Miller and Lorin Bachmann, PhD, DABCC, associate professor of pathology, Virginia Commonwealth University Medical Center, are leading a standardization initiative. “The NKDEP and International Federation of Clinical Chemistry and Laboratory Medicine have formed a joint Laboratory Working Group to facilitate standardization efforts for urine albumin,” says Dr. Bachmann, who chairs the IFCC Working Group for Standardization of Albumin in Urine. The aim is “a robust reference system so the manufacturers have a trusted accuracy base on which to calibrate their clinical assays,” says John H. Eckfeldt, MD, PhD, former chair and current member of the NKDEP Laboratory Working Group and a professor of laboratory medicine and pathology, University of Minnesota.

How far off the mark are manufacturers’ assays? A study that Dr. Miller, Dr. Bachmann, and colleagues conducted found as much as a 45 percent difference among the various commercial urine albumin procedures (Bachmann LM, et al. Clin Chem. 2014;60[3]:471–480).

“Most of the difference,” Dr. Bachmann says, “could be accounted for by concentration-dependent bias, where the methods differed by a range of -35 to +35 percent at 15 mg/L and -15 to +18 percent at 30 mg/L.”
That means patients who are near the ACR cutpoint of 30 mg/g could be classified as being above or below that threshold based on the laboratory method used rather than actual physiology, Dr. Miller says. “There’s a lot of evidence that suggests that the threshold should actually be lower. There’s an increased hazard ratio for progressing CKD at lower albumin/creatinine ratios, but the bias becomes even larger at lower values. So until the standardization is complete,” he says, “it’s not really practical from a clinical implementation point of view to consider lowering the thresholds.”

Dr. Miller predicts standardization will be wrapped up in about six years. The best route for now may be for clinicians to use the same laboratory for urine albumin testing when monitoring a patient who, for example, has diabetes, hypertension, or increased cardiovascular risk, he says. “The advantage of using the same lab is then you see changes that probably reflect the patient rather than the lab method. If you are tracking a diabetic who doesn’t yet have albumin in their urine, you could make a case that you should try two or three labs to see if one of them gives you a value above 30 mg/g as an early indicator, but it’s not a practical recommendation.”

Dr. Narva

Dr. Narva

Diurnal variation and many physiological parameters that affect urine albumin levels also can cause albumin/creatinine ratio results to vary. Dr. Narva points out that the Centers for Disease Control and Prevention’s evaluation of NHANES (National Health and Nutrition Examination Survey) data found that only 43 percent of the participants with a positive random urine exceeding 30 mg/g of creatinine had a positive first void specimen. That information was useful, he says, because the timing of the two specimen collections reflects the usual clinical scenario in which a screening test is performed on a random basis and a confirmatory one on a first morning void.

“It would be nice to have a random followed up by two first voids in a study to confirm that’s the way to do it,” Dr. Narva says. “As part of the urine albumin standardization process, the Lab Working Group will provide data on the best timing for reproducibility.” The CDC data will be useful in that regard, he adds.

In the use of glomerular filtration rate to diagnose CKD, Dr. Narva finds there’s confusion about the difference between measured and estimated GFR. He notes that the estimated GFR equations were developed in populations of people who had their GFRs measured. “They do provide a very good reflection of the population, but when you are looking at an individual across the desk or exam table from you, the uncertainty associated with the prediction equation result for that individual can be a significant matter,” he cautions. “The performance characteristic that’s used is P30, which is the likelihood of being within [plus or minus] 30 percent of the measured GFR. That’s a pretty wide range, and it increases as eGFR increases. So you can be telling someone they have CKD when actually they do not.”

The most useful aspect of the estimated GFR, he says, is identifying those with CKD who have a near normal creatinine. “People often don’t understand that the creatinine doesn’t have to be very high for the GFR to be much decreased. If someone sees a creatinine of three, they know that person has a problem. Its greatest purpose is as a warning flag that someone actually may have kidney disease.”

The 2012 Kidney Disease: Improving Global Outcomes recommendations, released in January 2013, advise using cystatin C for patients who have an eGFR based on creatinine that falls between 45 and 59 without elevated urine albumin. “That’s sort of an ambiguous area,” Dr. Miller says, “and basing the eGFR on a cystatin C-based equation or ideally on a combined creatinine and cystatin C equation gives a more reliable estimate of GFR.”

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