Elevated microalbuminuria within the “normal-range” predicts mortality in patients with stable angina
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November 27, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [1]
“Boston, MA”
A new analysis of the Prevention of Events with ACE Inhibition (PEACE) trial has demonstrated that microalbuminuria in the normal range was associated with increased mortality in patients with stable coronary artery disease. Elevated albumin excretion predicts cardiovascular risk independent of impaired glomerular filtration rate (GFR).
Normal albumin excretion is defined as less than 20 mg/day. Most dipsticks will not detect protein until excretion rates reach 300 mg/day. Excretion rates between 30 and 300 mg/day are defined as microalbuminuria. This corresponds to a spot urinary albumin to creatinine ratio (ACR) of 30 to 300 mcg/mg. There is clear evidence that microalbuminuria is associated with increased cardiovascular risk, and from the LIFE trial it is clear that substantial improvement in albuminuria is associated with improved outcomes. Recent studies, including the LIFE, HOPE, and PREVEND trials, have demonstrated that microalbuminuria which is elevated but within the normal range is also a marker for increased cardiovascular risk. There is growing consensus that albuminunia is a useful marker for the presence of vascular disease, and that risk is associated with albumin excretion in a continuous manner.
This study examined urinary ACR in all patients in PEACE who had contributed a urine sample (n = 2977 at baseline, n=1339 at mean 34 month follow-up). They divided normal range microalbuminuria into sex-specific categories: lowest normal (<5 for both sexes), low-normal (5.0-7.7 in women and 5.0-6.6 in men), medium normal (7.7-11.5 in women and 6.6-9.5 in men), and high-normal (11.5-25 in women and 9.5-17 in men). Event rates were then determined, adjusting for baseline covariates including treatement group (placebo vs.trandolapril), age, sex, history of myocardial infarction, diabetes, hypertension, low ejection fraction, smoking, GFR, and body mass index.
After adjusting for covariates, there was a statistically significant trend towards increased cardiovascular death (p=0.01) and all-cause mortality (p<0.001) with increasing levels of normal-range albuminuria. Medium-normal range ACR was associated with increased all-cause mortality (OR 1.77; CI 1.07 to 2.93). Interestingly, there was no interdependence noted between ACR and GFR. Risk increased in a linear manner in patient with low GFR and patients with high GFR. Event rates were low in this relatively healthy group of patients, and there was no association found between trandolapril treatment benefit and ACR level. However, trandolapril therapy did decrease ACR (12.5 vs. 14.6 mcg/mg at follow-up; p=0.0001) and previous studies have shown that decreases in ACR improve outcomes. Consistent with previous studies, patients with increases in ACR over the mean 34-month follow-up were at high risk for cardiovascular death (HR 1.74 per unit log ACR).
There is increasing evidence that proteinuria well below the level that would be detected by dipstick is associated with increased cardiovascular risk. The evidence suggests that the definition of “normal” albumin excretion should be redefined, as clearly levels of albuminuria within the current normal range predict cardiovascular risk. The PEACE analysis is helpful in this regard, as it defined clear sex-specific categories of albuminuria and demonstrated that elevated ACR is useful for risk prediction independent of GFR. There are no recommendations for screening the general population for proteinuria at present. According to lead author Scott Solomon, "Cardiologists and primary care physicians need to be more aware that both measures of renal dysfunction - either reduced GFR or albuminuria – place patients at increased risk. An estimated GFR below 60 or any degree of albuminuria places a patient at increased risk and will identify patients who might benefit from more aggressive therapies."
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