In this study we investigated the relationship between UACR and long-term cardiovascular and noncardiovascular mortality risk in the general population. Our results showed that the traditional UACR cutoff (30 mg/g) is suitable for predicting long-term noncardiovascular mortality risk in the community; however, setting the cutoff value at 16 mg/g may have greater sensitivity for identifying individuals with high cardiovascular mortality risk.
Albuminuria, which is often caused by increased glomerular permeability or impaired reabsorption by proximal tubule epithelial cells, is significantly associated with cardiovascular and noncardiovascular mortality.[19–21] However, a recent study of 31,413 U.S. adults showed that even a slightly elevated UACR that was still within the normal range (30 mg/g) was associated with a significantly higher cardiovascular mortality; and a meta-analysis of albuminuria in the general population also found that individuals with UACR in the range of 10 to 29 mg/g had a higher risk of all-cause and cardiovascular mortality compared to those with a ratio of 5 mg/g. These reports cast doubt on the suitability of the traditional UACR cutoff (30 mg/g) for long-term mortality prediction. However, previous studies did not explore optimal UACR cutoffs, and the values used to assess long-term cardiovascular mortality risk were inconsistent. In the Reasons for Geographic and Racial Differences in Stroke (REGARDS) trial, UACR was categorized as <10 mg/g, 10 to <30 mg/g, 30 to 300 mg/g, and >300 mg/g. However, in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) study that explored the association between baseline UACR and cardiorenal outcome, UACR was categorized as 0, >0 to <15, 15 to <30, 30 to <100, 100 to <300, and ≥300 mg/g.
We observed a strong linear relationship between log-transformed UACR and cardiovascular mortality. This can be explained as follows. Firstly, inflammation and oxidative stress are known to be key pathophysiologic roles in atherosclerosis, and recent studies have demonstrated a positive correlation between inflammatory and oxidative stress markers such as interleukin (IL)-2, IL-6, and superoxide dismutase and UACR.[23, 24] Therefore, low-grade inflammation in patients with increased UACR may contribute to atherosclerotic plaque development and progression, leading to late clinical complications. Secondly, elevated UACR was shown to be associated with left ventricular hypertrophy, which increases the risk of decompensated heart failure and ventricular arrhythmia; this in turn increases the risk of cardiovascular mortality 4 fold. Thirdly, a previous study showed that elevated UACR was associated with higher levels of coagulation factors; this increased the risk of thrombosis, which is among the most common causes of cardiovascular mortality.
Based on the linearity between UACR and cardiovascular mortality, we explored the predictive value of different UACR cutoffs. We found that setting the cutoff at 16 mg/g instead of 30 mg/g was more advantageous for identifying individuals with higher cardiovascular mortality risk in the general population. This raises the question of why the cutoff value that differentiates high and low risk of cardiovascular mortality deviated to the left of 30 mg/g. One explanation is that increased urinary albumin excretion and cardiovascular disease development share a common pathologic mechanism—namely, endothelial dysfunction, which could increase glomerular permeability to macromolecules such as albumin and result in increased urinary albumin excretion.[20, 28, 29] Endothelial dysfunction also contributes to the development of coronary artery disease, heart failure, etc. Because of the close relationship between urinary albumin excretion and cardiovascular disease, cardiovascular mortality risk may be more sensitive to small increases in UACR. Additionally, in the cohort analyzed in this study, there was a high prevalence of hypertension and diabetes mellitus; in these patients, a slight increase in UACR may be a sign of target organ damage, which can significantly increase cardiovascular mortality.[30, 31]
The linearity observed between log-transformed UACR and noncardiovascular mortality has a few possible explanations. A longitudinal observational study conducted in Australia showed that in individuals with normoalbuminuria, UACR was significantly associated with glomerular hyperfiltration, which plays an important role in the induction of renal damage. Individuals with glomerular hyperfiltration also have a higher risk of mortality from noncardiovascular causes such as infection or liver failure. On the other hand, increased UACR was found be associated with increased cancer mortality, which accounted for a large proportion of noncardiovascular death in our analysis. The UACR cutoff of 30 mg/g was ideal for predicting noncardiovascular mortality.
There were several limitations to this study that should be noted. Firstly, the UACR was calculated from a single, untimed urine collection, and therefore did not reflect changes in urinary albumin excretion over the course of the day. Secondly, because of the retrospective study design, our findings should be interpreted with caution. Finally, although the models were adjusted for potential risk factors using multiple regression analysis techniques, there may have been some residual confounding factors.