Should Normal Range of Albumin Be Redefined for Cardiovascular Health?

Growing evidence points to kidney health as a major contributor to cardiovascular health, with the implication that there should be more testing and treatment for albuminuria starting in the current normal range.

The death risks of suboptimal cardiovascular health and a urinary albumin-to-creatinine ratio (UACR) in the high end of normal (<30 mg/g) were magnified when the two were put together, Xueli Yang, PhD, of Tianjin Medical University, China, and colleagues found from National Health and Nutrition Examination Survey (NHANES) data.

In addition to a near-linear correlation between UACR and risk of all-cause mortality, there appeared to be a significant multiplicative interaction of UACR and cardiovascular health such that mortality risk was especially high in people with high-normal UACR and moderate and poor cardiovascular health.

“The findings indicate that UACR elevation within the normal range may mediate 10.5% of the associations between poor CVH [cardiovascular health] and all-cause mortality, which further supports the importance of kidney function evaluation, particularly among populations with high cardiovascular risk,” the investigators reported in JAMA Network Open.

“Although further validation among independent populations is warranted, these findings underscore the importance of early identification of high-risk populations with normal UACR values through assessment of CVH, which might be helpful to target risk interventions in the future,” they concluded.

This is in line with UACR above normal being a known cardiovascular risk marker. Additionally, prior work had found albuminuria within the normal range to be tied to increased cardiovascular risk.

Recently, the AHA introduced cardiovascular-kidney-metabolic (CKM) syndrome as a health disorder covering overlaps in obesity, diabetes, chronic kidney disease, and cardiovascular disease. An estimated one in three U.S. adults have three or more risk factors of CKM syndrome.

Ladan Golestaneh, MD, MS, of Albert Einstein College of Medicine/Montefiore Medical Center in the Bronx, New York, commented that the bar for normal urinary albumin may need to be changed.

“Below the current cut off of 30 mg/g clinicians do not consider urinary albumin in any range as a factor in clinical decision making. Nor do they consider a high versus low range of urinary albumins below this cutoff as a meaningful risk marker. Clinicians may need to consider higher urinary albumins in the normal range as a risk marker for cardiovascular outcome at the very least,” she told MedPage Today.

“Future treatment guidelines may recommend treating within normal range higher albuminuria,” she added.

Yet there is a problem of inadequate testing for albuminuria in clinical practice in the first place, according to George Bakris, MD, of University of Chicago, who noted that only one in three people who need testing — namely people with type 2 diabetes and those with documented kidney disease — are actually getting it done.

“[Albuminuria] is not being measured in people that clearly need it, let alone people that do not have diabetes or kidney disease,” stressed Bakris, who was not involved with the study.

For this cohort study, Yang’s group analyzed seven continuous cycles of NHANES from 2005 through 2018 and linked mortality records up to 2019 for this nationally representative sample of U.S. adults who had supplied urine specimens at the time of survey completion.

The study cohort included 23,697 adults younger than 80 years with a normal UACR. Mean age was 45.6 years, and the cohort was roughly split between the sexes. By race, 10% were Black and 13.3% Hispanic.

Researchers treated UACR as a continuous variable. They also classed patients by tertiles of UACR: low-normal (<4.67 mg/g), medium-normal (4.67-7.67 mg/g), and high-normal (7.68-30 mg/g).

Cardiovascular health was scored according to the Life’s Essential 8 checklist — comprising diet quality, physical activity duration, smoking status, sleep duration, body mass index, blood lipids, blood glucose, and blood pressure — from the American Heart Association. NHANES participants were grouped as having poor (0-49 points), moderate (50-79 points), and ideal (80-100 points) cardiovascular health.

Over a median 7.8 years of follow-up, compared with the low UACR group, high UACR in the normal range was associated with increased mortality risk in the moderate CVH (HR 1.54, 95% CI 1.26-1.89) and poor CVH groups (HR 1.56, 95% CI 1.10-2.20).

It is still unclear how mechanistically high-normal UACR can lead to poor outcomes.

“Risks tend to multiply so individuals at high risk for other reasons have a higher incremental risk for the same elevation in albuminuria, providing a greater opportunity for risk reduction,” reasoned Josef Coresh, MD, PhD, of Johns Hopkins University, who was also not involved with the study.

“Some research has indicated that the increased kidney endothelial permeability associated with microalbuminuria may be a sign of diffuse endothelial dysfunction, leading to cardiovascular damage and elevated risk of death. The UACR within the normal range or microalbuminuria may also induce alterations in von Willebrand factor, fibrinogen, and thrombomodulin,” Yang and colleagues wrote.

They acknowledged that their study relied on just one spot urine measurement, which does not account for daily variations in albuminuria. “More studies with multiple urine measurements, preferably of the first morning void, may help with determining a threshold to estimate early kidney function damage,” they suggested.

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