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Albuminuria is a well-documented predictor of cardiovascular (CV) mortality. However, day-to-day variability is substantial, and there is no consensus on the number of urine samples required for risk prediction. To resolve this we followed 9158 adults from the population-based Nord-Trøndelag Health Study for 13 years (Second HUNT Study). The predictive performance of models for CV death based on Framingham variables plus 1 versus 3 albumin-creatinine ratio (ACR) was assessed in participants who provided 3 urine samples. There was no improvement in discrimination, calibration, or reclassification when using ACR as a continuous variable. Difference in Akaike information criterion indicated an uncertain improvement in overall fit for the model with the mean of 3 urine samples. Criterion analyses on dichotomized albuminuria information sustained 1 sample as sufficient for ACR levels down to 1.7 mg/mmol. At lower levels, models with 3 samples had a better overall fit. Likewise, in survival analyses, 1 sample was enough to show a significant association to CV mortality for ACR levels above 1.7 mg/mmol (adjusted hazard ratio 1.37; 95% CI 1.15-1.63). For lower ACR levels, 2 or 3 positive urine samples were needed for significance. Thus, multiple urine sampling did not improve CV death prediction when using ACR as a continuous variable. For cutoff ACR levels of 1.0 mg/mmol or less, additional urine samples were required, and associations were stronger with increasing number of samples.

Background: The association between albuminuria and coronary heart disease (CHD) is well-known, but uncertainties related to day-to-day variability and effect modification of gender complicate the risk assessment process. This study evaluates the associations of CHD with albuminuria level in men and women based on the number of urine samples. Methods: Nine thousand one hundred and fifty-eight adults provided 3 urine samples and were followed for 14 years in the population-based HUNT-2 cohort study. The association of myocardial infarction or coronary death with different albumin-creatinine ratio (ACR) cut-offs, based on gender and number of positive ACRs, were estimated by hazard ratios (HRs) and adjusted for by Framingham variables. Results: Associations between ACR and CHD were similar in men and women. For example, HRs for moderately increased (3.0≤ ACR ≤30.0 mg/mmol) vs. normal albuminuria (ACR <1.0 mg/mmol) were 1.40 (95% CI 1.27-2.03) and 1.61 (95% CI 1.15-1.71) respectively, (p_sex-equality = 0.3). However, median intra-individual day-to-day ACR coefficient of variation was 22.4% in women vs. 17.5% in men (p < 0.001). Two or 3 positive ACRs were required to establish a significant association with CHD at levels below 4.0 mg/mmol in women, while one positive ACR implied a significant association at all levels in men. Based on receiver-operating-characteristics curves, the Youden index suggested possible equal cut-offs for women (1.12 mg/mmol) and men (0.88 mg/mmol), p = 0.06. Conclusions: There were no significant gender differences in the association between albuminuria and coronary events. However, women had increased intra-individual albuminuria variability compared to men, necessitating several positive urine samples if mildly increased albuminuria is used in coronary risk evaluation.

Both increasing and decreasing albuminuria are significant independent predictors of mortality in nondiabetic individuals, but must be interpreted in light of baseline values. Cutoffs and clinical usefulness in nondiabetic study participants should be further investigated.

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