College of American Pathologists
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Getting serious about microalbuminuria

August 2004
Rosemary Frei

Cardiologists, nephrologists, and other physicians are intent on expanding the use of urine albumin screening in high-risk patients and having the right diagnostic devices to do so.

Experts gathered in New York in May at an international symposium to reach consensus on the significance of microalbuminuria, how it should be measured, and what’s needed to reduce it. Even a small amount of albumin in the urine, they say, is a more robust marker for elevated risk of developing cardiovascular disease, diabetes, and kidney disease than either elevated blood pressure or cholesterol.

"Albumin in your urine is bad for you—and it’s even outweighing those other two parameters, by far," Dick de Zeeuw, MD, PhD, who chaired the symposium on the role of albuminuria in health and disease, told CAP TODAY. "At our meeting we had a consensus that it is a risk marker, that it’s independent of all the other risk markers, and that it should be lowered by therapeutics that we have and that will be developed, in order to lower the risk of cardiovascular and renal disease."

A followup conference will take place in Europe next year to build on the consensus and set targets for intervention.

Microalbuminuria is now widely acknowledged as an independent predictor of diabetes, stroke, myocardial infarction, kidney failure, and death. Moreover, a relatively large percentage of people suffer from microalbuminuria. Dr. de Zeeuw, professor and head of the Department of Clinical Pharmacology at the Groningen University Medical Center, the Netherlands, participated in a community-based study that demonstrated that 7.2 percent of the 40,458 people surveyed had microalbuminuria, defined as a urinary albumin concentration of 20-200 mg/L (Hillege HL, et al. Circulation. 2002; 106: 1777-1782).

Dr. de Zeeuw and his colleagues also found the risk of cardiovascular and noncardiovascular death varied directly with urinary albumin levels. People with urinary albumin levels of 0-10 mg/L had a cardiovascular mortality rate of 1.2 per 1,000 person-years and a noncardiovascular mortality rate of 2.3 per 1,000 person-years. Those with microalbuminuria, or greater than 200 mg/L, had cardiovascular and noncardiovascular mortality rates of 16.6 and 12.5 per 1,000 person-years, respectively. The investigators calculated using a multiple regression analysis that a doubling of urinary albumin concentration is associated with a 1.29-fold increased risk of cardiovascular mortality and a 1.12-fold increased risk of noncardiovascular death.

An earlier study of the risk of cardiovascular events, death, and heart failure associated with albuminuria in diabetics and nondiabetics showed microalbuminuria increases the adjusted relative risk of major cardiovascular events by 1.83-fold (Gerstein HC, et al. JAMA. 2001; 286: 421-426). The researchers also found that microalbuminuria increases the adjusted relative risk of all-cause mortality by 2.09-fold, and that these increases apply to people with and without diabetes mellitus. Furthermore, they showed that for every 0.4 mg/mmol increase in albumin/creatinine levels, the adjusted risk of major cardiovascular events rises by nearly six percent.

Other studies have shown, in parallel, that albuminuria has a key role to play in predicting renal outcome in more advanced stages of diabetic nephropathy.

These results underscore that there is an increased risk of kidney and cardiovascular disease even at microalbumin levels previously considered to be normal, Dr. de Zeeuw says. The mechanism behind this relationship is still not fully known. It appears to relate to endothelial dysfunction and the consequent leakage of albumin into tissue, where it can cause damage.

This disease mechanism has begun to spiral out of control in the Western world, with rates of microalbuminuria skyrocketing, accompanied by diabetes and kidney failure. Symposium speaker Robert Atkins, MD, DSc, and his colleagues demonstrated in the large Australian Diabetes, Obesity and Lifestyle Study that the number of people with diabetes has tripled since 1981. Moreover, says Dr. Atkins, director of the Department of Nephrology at Monash Medical Center, Melbourne, and former president of the International Society of Nephrology, the number of diabetics in the world is expected to double by 2020.

"This is alarming in that the shift has just happened over the last 15 years. . . . It’s the pace of change affecting the kidneys that’s important," Dr. Atkins told CAP TODAY. "What we’re now seeing all over the world is that diabetes is the main cause of chronic kidney disease, and this is being driven by proteinuria and albuminuria."

Therapeutic efforts should focus, then, on lowering urinary albumin levels. The salubrious effects of hypertension-reducing medications may be due in large part to the fact that they lower microalbumin levels, Dr. de Zeeuw observes.

"Microalbuminuria indicates an early stage of cardiovascular or renal disease and/or risk, and thus early intervention would confer better renal and cardiovascular protection," he says. Moreover, early intervention appears to be cost-effective, he adds, and may be necessary in the absence of other available interventions that provide as much benefit as focusing on albumin levels. "This all makes it very necessary to do something, and to start thinking about intervention strategies."

Drs. de Zeeuw and Atkins strongly support screening high-risk patients for microalbuminuria, which they note is feasible because sensitive assays are available in North America and Europe. The American Diabetes Association recommends screening for microalbuminuria three times within a three- to six-month period and that intervention be initiated if two of the three measurements are 20 mg/L (Diabetes Care. 2003; 26 [Suppl. 1]: S94- S98). Those with diabetes and hypertension should be screened annually.

The principal techniques for measuring microalbumin have involved various permutations and combinations of formation and detection of albumin-human antibody complexes or dye-albumin complexes. The HemoCue Urine Albumin System, distributed in the U.S. by HemoCue, Lake Forest, Calif., detects albumin-antibody complexes photometrically. The device, which has been used in Europe for two years, is small and can be used on physicians’ desktops for results within minutes. The company is preparing the FDA 510(k) application now and expects to make the product available in the U.S. later this year.

The system consists of a small benchtop photometer, a transformer, and a cuvette. The user first fills the cuvette by immersing the tip into the sample, then places it in the analyzer’s cuvette holder. The quantitative urine albumin result is displayed within 90 seconds. The HemoCue system has a range of 10-150 mg/L and an intra-assay coefficient of variation of about five percent, according to Lena Wahlhed, an international product specialist in HemoCue’s headquarters in Angelholm, Sweden.

Says Dr. de Zeeuw, "You put the urine in the machine, and a minute later you have the result. That is what we need in general practice."

He notes that Bayer Diagnostics, Tarrytown, NY, manufactures a similar system for point-of-care use. The DCA 2000+ Analyzer, available in the U.S., yields a reading in 10 minutes. A specific antibody complex is formed with the urinary albumin, and the increased turbidity is measured at a wavelength of 531 nm. The intra-assay CV in a urine albumin range of 6.7-244.8 mg/L is 2.7-4.9 percent, while the inter-assay CV is 3.4-4.1 percent.

Dr. de Zeeuw and his colleagues used the BN II for their community-based study reported in Circulation. This device, made by Deerfield, Ill.-based Dade Behring, uses nephelometry to determine the density of the antibody-antigen complexes and is designed for laboratory use.

The BN II has a sensitivity of 2.3 mg/L and inter- and intra-assay coefficients of variation of 4.4 percent and 4.3 percent, respectively. Its effective sample throughput is about 130 tests per hour, and it is designed for use with the Power Macintosh G3/350.

Microalbumin testing has been available for many years on Dade Behring’s BN II and BN ProSpec systems, both of which use nephelometric technologies based on measuring light scatter, says Jim Meenan, marketing manager for plasma proteins at Dade Behring, Glasgow, Del. "Nephelometric systems are considered by many to have significant advantages in sensitivity and low-end precision over other methods," he says.

Dade Behring introduced microalbumin last month on its Dimension clinical chemistry systems. "Our Dimension assay has the reliability of particle-enhanced turbidimetric inhibition immunoassay technology, or PETINIA, which allows direct quantitation in urine samples," Meenan says.

Accumin, made by New York-based AusAm Biotechnologies, is a direct method for detecting intact urine albumin, based on high-performance liquid chromatography. Accumin’s HPLC separates urine into its constituent parts and determines albumin count by measuring physical molecule size. Accumin was able to identify microalbuminuria in diabetics three years earlier on average and up to 12 years earlier than radioimmunoassay or turbidimetry, according to a study published recently (Comper WD, et al. Kidney Int. 2004;65: 1850- 1855). Wayne Comper, PhD, DSc, AusAm’s chief scientific officer, says HPLC doesn’t show microalbuminuria in normal patients and that the standard microalbumin reference ranges of 30 mg/g creatinine to 300 mg/g creatinine do not need to be changed when Accumin is used.

Dr. Atkins presented data at the international symposium in May from 6,000 patients in the Australian Diabetes, Obesity and Lifestyle Study indicating the AusAm technology is more sensitive to albumin, particularly at low concentrations, than nephelometry. For example, 2.6 percent of the subjects—who had neither diabetes nor hypertension—were found to have albumin in the urine with conventional testing, but the AusAm method indicated 11.8 percent had microalbuminuria. Of the 496 diabetics tested so far in the study, Accumin identified microalbuminuria in 42 percent versus 21 percent for nephelometry.

"That is advancing us again, in terms of measurement, because it picks up about double the amount of albumin in the lower ranges," Dr. de Zeeuw says.

AusAm received FDA clearance for Accumin in August 2003, and it’s available in the U.S. as of this summer at Specialty Laboratories in Santa Monica, Calif.; Esoterix in Austin, Tex.; St. Raphael’s Hospital in New Haven, Conn.; Genesis Diagnostics in Chicago; and elsewhere.

"So there is concerted action happening," Dr. de Zeeuw says. "There are people working in biochemistry, pathology, that are working on measuring and detecting albumin, to get advances in this whole area."

He says more physicians and patients have to become aware of the risk and what to do about it. "It’s been floating around for ages already," he says. "It’s been there too long without success."

Rosemary Frei is a writer in Toronto.