Normoalbuminuria—is it normal? The association of urinary albumin within the ‘normoalbuminuric’ range with adverse cardiovascular and mortality outcomes: A systematic review and meta-analysis

Aim: To assess the association between urinary albumin-to-creatinine ratio (UACR) categories within the normal range with mortality and adverse cardiovascular outcomes. Materials and Methods: PubMed and Embase were systematically searched for real-world evidence studies. Studies were manually evaluated according to predefined eligibility criteria. We included prospective and retrospective cohort studies of the association between UACR categories <30 mg/g and cardiovascular outcomes or mortality. Published information regarding study design, participants, UACR categorization, statistical methods, and results was manually collected. Two UACR categorization approaches were defined: a two-category (UACR <10 mg/g vs. 10-30 mg/g) and a three-category division (UACR <5 mg/g vs. 5-10 and 10-30 mg/g). A random effects meta-analysis was performed on studies eligible for the meta-analysis. Results: In total, 22 manuscripts were identified for the systematic review, 15 of which were eligible for the meta-analysis. The results suggest an association between elevated UACR within the normal to mildly increased range and higher risks of all-cause mortality, cardiovascular death, and coronary heart disease, particularly in the range of 10-30 mg/g. Compared with UACR <10 mg/g, the hazard ratio [HR (95% confidence interval, CI)] for UACR between 10 and 30 mg/g was 1.41 (1.15, 1.74) for all-cause mortality and 1.56 (1.23, 1.98) for coronary heart disease. Compared with UACR <5 mg/g, the risk of cardiovascular mortality for UACR between 10 and 30 mg/g was more than twofold [HR (95% CI): 2.12 (1.61, 2.80)]. Intermediate UACR (5-10 mg/g) was also associated with a higher risk of all-cause mortality [HR (95% CI): 1.14 (1.05, 1.24)] and cardiovascular mortality [HR (95% CI): 1.50 (1.14, 1.99)]. Conclusions: We propose considering higher UACR within the normoalbuminuric range as a prognostic factor for cardiovascular morbidity and mortality. Our findings underscore the clinical significance of even mild increases in albuminuria.