Urinary Albumin
Authors: Jiang He, Jing Chen
Journal: Journal of the American Society of Nephrology (2012)

CKD is not only a major cause of ESRD but also cardiovascular disease and premature death.1–3 Prospective cohort studies document that macroalbuminuria (urinary albumin >300 mg/24 h or >200 μg/min) and microalbuminuria (urinary albumin 30–300 mg/24 h or 20–200 μg/min) associate with increased risk of cardiovascular disease in the general population3–5 and in patients with diabetes.6,7 Furthermore, prospective cohort studies indicate that the association between urinary albumin and risk of cardiovascular disease is continuous without threshold effects, and is independent from other cardiovascular disease risk factors.4,6,8 The Chronic Kidney Disease Prognosis Consortium pooled data from 105,872 participants (730,577 person-years) from 14 studies to examine the association between urinary albumin/creatinine ratios (ACRs) and mortality from cardiovascular disease and all causes.8 Compared with an ACR of 5 mg/g, hazard ratios (HRs) and 95% confidence intervals (95% CIs) were 1.20 (1.15–1.26), 1.63 (1.50–1.77), and 2.22 (1.97–2.51) for all-cause mortality at ACRs of 10, 30, and 300 mg/g, and 1.13 (1.07–1.20), 1.55 (1.30–1.86), and 2.59 (1.95–3.44) for cardiovascular mortality, respectively, after adjusting for age, sex, race, history of cardiovascular disease, systolic BP, serum total cholesterol, diabetes, cigarette smoking, and estimated GFR.8,9 This issue of JASN presents a report by Piero Ruggenenti and the Bergamo Nephrologic Diabetes Complication Trial (BENEDICT) study investigators on the relationships between urinary albumin and long-term cardiovascular events in 1208 hypertensive type 2 diabetic patients with normal urinary albumin who participated in the BENEDICT trial.10 This study is unique because all study participants had a urinary albumin <20 μg/min (30 mg/24 h) in two of three overnight urine collections at the baseline examination. A continuous nonlinear relationship between urinary albumin and combined cardiovascular events was observed without thresholds.10 A one-unit increase in urinary albumin (1 μg/min or 1.44 mg/24 h) was independently associated with a 5% increase in cardiovascular events (HR, 1.05; 95% CI, 1.02–1.08) after adjusting for age, sex, duration of diabetes, cigarette smoking, history of cardiovascular disease, body mass index, hemoglobin A1c, randomization to angiotensin converting enzyme (ACE) inhibitor therapy during the trial, mean arterial pressure, serum creatinine, LDL/HDL cholesterol ratio, triglycerides and uric acid levels, and treatment with lipid lowering therapy. Furthermore, the excess risk of cardiovascular disease (HR, 1.02; 95% CI, 1.01–1.04) was observed in individuals with a urinary albumin of 1–2 μg/min (1.44–2.88 mg/24 h) compared with those with a urinary albumin <1 μg/min (<1.44 mg/24 h). These data confirm a continuous association between urinary albumin and increased risk of cardiovascular disease. Moreover, this study indicates that any degree of measurable urinary albumin increases risk of cardiovascular disease. Therefore, there is no normal measurable urinary albumin. However, one must bear in mind that these data are from an observational study conducted in patients with hypertension and diabetes. It is possible that measurable urinary albumin reflects residual and unmeasured confounding effects. In addition, repeated measures of urinary albumin were not available, and the longitudinal relationship between changes in urinary albumin and risk of cardiovascular disease cannot be investigated. Finally, it remains unknown whether this relationship between urinary albumin and risk of cardiovascular disease is the same in the normotensive nondiabetic population. Another interesting finding from this study is that the association between urinary albumin and risk of cardiovascular disease disappeared among the trial participants who were originally assigned to ACE inhibitor therapy.10 This finding is not entirely expected because all trial participants received ACE inhibitor therapy during the average 9.2 years of post-trial follow-up. A statistical test for interaction between initial treatment assignments in the BENEDICT trial and urinary albumin on the risk of cardiovascular events was not performed. Therefore, one cannot exclude the possibility that this observation was due to chance alone. There is strong evidence that treatment of microalbuminuria and macroalbuminuria with ACE inhibitors or angiotensin II–receptor blockers slows the progression of kidney disease.11,12 In a meta-analysis of 85 randomized controlled trials (21,708 patients), there is a significant reduction in the development of ESRD, progression of microalbuminuria to macroalbuminuria, and risk of nonfatal cardiovascular disease with ACE inhibitors versus placebo.11 However, there was no significant reduction in deaths from all-cause mortality or cardiovascular disease with ACE inhibitors versus placebo.11 The recent US Preventive Services Task Force Report indicates that ACE inhibitors (relative risk [RR], 0.65; 95% CI, 0.49–0.88) and angiotensin II–receptor blockers (RR, 0.77; 95% CI, 0.66–0.90) reduce ESRD versus placebo in stage 1–3 diabetic patients with CKD and macroalbuminuria.12 ACE inhibitors reduce mortality versus placebo (RR, 0.79; 95% CI, 0.66–0.96) in patients with microalbuminuria and cardiovascular disease or high-risk diabetes.12 Given the observational design, this study cannot recommend treating patients with a measurable urinary albumin within normal range (<30 mg/24 h). However, this study can generate hypotheses for further clinical trials. Cost-effectiveness must be taken into account if a randomized controlled trial is to tackle this issue. Disclosures None.