Urinary Albumin Excretion as a Predictor of the Development of Hypertension in the General Population

Materials and Methods

Results and Discussion

We observed 19592 person-years during a mean follow-up of 4.2 yr. In this time, 413 (8.9%) participants of our population developed hypertension, giving an incidence rate of 21/1000 person-years. Compared with participants who remained normotensive during follow-up, participants who developed hypertension were generally older, with an unfavorable cardiovascular risk profile, including higher SBP and DBP and decreased GFR (Table 1). UAE was increased in participants who developed hypertension. Accordingly, the incidence of hypertension was higher with higher baseline levels of UAE (Figure 1).

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Figure 1.

Baseline urinary albumin excretion (UAE) and incidence of hypertension after 4.2 yr of follow-up. Incidence is given according to clinical categories of UAE at baseline (P < 0.001 for trend). Numbers in the bars indicate the number of individuals within the category. When we subdivided the population according to tertiles of UAE at baseline (<6.5, 6.5 to 10.5, and >10.5, respectively), a similar trend was seen, with an incidence of hypertension of 6.5, 8.3, and 11.9% from the lowest to the highest tertiles, respectively (P < 0.001 for trend).

When baseline UAE was entered in a logistic regression model with hypertension as dependent variable, UAE significantly predicted development of hypertension with an OR of 1.43 (95% CI 1.28 to 1.60) per 1 Ln(UAE) unit of change. This equals an OR of 2.29 (95% CI 1.77 to 2.95) for each 10-fold increase of UAE. After adjustment for age and gender; baseline values of SBP, DBP, and GFR; and other possible confounders, the association between UAE and the development of hypertension remained significant (Table 2).

In the final model, a significant interaction was found between UAE and GFR (Table 2, model 5). To explore this interaction, we repeated our final model in strata according to tertiles of GFR. Results for UAE in the three strata of GFR were OR 1.93 (95% CI 1.26 to 2.97), OR 0.84 (95% CI 0.41 to 1.71), and OR 1.16 (95% CI 0.54 to 2.49) per 10-fold increase of UAE in the lowest to highest tertiles, respectively. The interaction between UAE and GFR is illustrated in Figure 2. This graph shows that UAE predicts the development of hypertension most strongly when renal function is low, indicating synergism. When renal function is higher, the risk that is added by an increased UAE diminishes.

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Figure 2.

Incidence of hypertension after 4.2 yr of follow-up by categories of albuminuria and tertiles of GFR at baseline.

These findings are in contrast with current thinking that elevated UAE is secondary to development of high BP (2,10). One could argue that our observation is erroneous and caused by the presence of prehypertension in individuals with high UAE at baseline or by misclassification of individuals as normotensive at baseline as a result of variation in the BP measurement, whereas in fact they were hypertensive. Therefore, we first adjusted our models for baseline SBP and DBP. After these adjustments, the association between UAE and development of hypertension remained significant. Second, we repeated our analyses after adjustment for the presence of LVH at baseline. LVH is considered a marker of target organ damage in hypertensive individuals (2,10) and might indicate the presence of prehypertension or undiagnosed hypertension in individuals who are classified as normotensive. However, adjustment for the presence of LVH did not influence our finding that baseline UAE predicts the development of hypertension. Third, we excluded participants who had an SBP ≥135 and/or DBP ≥85 (n = 505) at baseline. This cutoff point was chosen to exclude individual who had the highest risk for being prehypertensive or misclassified as normotensive while maintaining an adequate number of cases. Again, this correction did not affect our results. Thus, our study shows that UAE predicts future development of hypertension, independent of other predisposing factors. The increased risk for hypertension associated with elevated UAE is higher when the GFR is lower.

Our results confirm the finding in the Framingham Offspring Study that urinary albumin concentration in a single morning void urine sample is associated with the risk for developing hypertension (13). However, in contrast to our study, the Framingham Offspring Study did not explicitly investigate the relation among UAE, renal function, and development of hypertension. Although the authors added to their statistical model baseline serum creatinine as a renal parameter to adjust for possible confounding by the presence of renal dysfunction, the use of serum creatinine as an estimate of renal function is not recommended (1,14). It is generally accepted that the inverse relation between serum creatinine and GFR is influenced by muscle mass and consequently by factors such as age, gender, and race. These factors should be taken into account using a validated formula.

The finding that baseline UAE predicts BP progression has been debated by the investigators of the HARVEST Study, who were not able to demonstrate such a relation (15,16). This conflicting data may be explained by the lower age of the population in the HARVEST Study (mean age 33 yr), compared with the age of our population (mean age 45 yr) or the population of the Framingham Offspring Study (mean age approximately 55 yr). A different mechanism may underlie the development of UAE in this young age group with low cardiovascular risk, with UAE for instance being more hemodynamically related, whereas UAE may be more associated with renal microvascular damage in the older age groups with higher cardiovascular risk.

We explain our findings as follows. Both lower GFR and higher UAE can have renal damage as the underlying cause (1). Thus, the presence of an interaction between these two variables in our model suggests that UAE predicts the development of hypertension as a result of the underlying presence of mild renal damage. It has been well established that the kidney plays a central role in the pathogenesis of hypertension in case of severe renal function impairment (1,17,18), but even in individuals with mild renal damage, this may be the case. Recent experimental studies in rats have shown that minor changes in the renal microvasculature and tubulointerstitium may lead to salt-sensitive hypertension (4–6), providing a possible pathway whereby mild renal damage can lead to the development of hypertension (19). Furthermore, as hypothesized by Brenner et al. (20), a reduction in glomerular filtration surface area, which may be reflected by a mildly reduced GFR, may lead to hypertension as a result of a limited ability to excrete sodium. Indeed, a recent autopsy study suggested that young hypertensive individuals may have a lower number of nephrons than age-matched normotensive control subjects (21), supporting Brenner’s hypothesis.

Although the studies mentioned above underscore the importance of the kidney in the pathogenesis of hypertension, the cause of hypertension is heterogeneous. UAE is suggested to be the result of damage to the renal microvasculature (1,22), but these local changes in turn may be part of generalized endothelial dysfunction (23). Indeed, generalized endothelial dysfunction has been suggested to play a role in the cause of hypertension (24,25). Thus, alternatively, the association between UAE and generalized endothelial dysfunction could explain our findings. To test for this possibility, we looked at the effect of hs-CRP on the association among UAE, renal function, and the development of hypertension in our logistic regression models, because hs-CRP has also been found to be associated with generalized endothelial dysfunction (26–28). Although baseline hs-CRP was univariately significantly associated with development of hypertension during follow-up (OR 1.24; 95% CI 1.17 to 1.32 per two-fold change of hs-CRP; P < 0.001), in the multivariate models, after adjustment for possible confounders, this association was no longer significant (final model P = 0.3). Furthermore, the presence of hs-CRP in the model did not influence the association among UAE, renal function, and the development of hypertension. Thus, in our opinion, it is less likely that the association of UAE with generalized endothelial dysfunction explains our findings.

Strengths of our study are the use of a large community-based cohort, use of 24-h urine samples to estimate UAE, use of data of community pharmacies to complement self-reported data on use of antihypertensive drugs, extensive adjustment for covariates that are associated with development of hypertension, and the possibility to explore different possible pathways to explain the association between UAE and the development of hypertension. Two limitations should be mentioned. First, the PREVEND cohort is selected from a mainly white population. Our findings therefore cannot simply be generalized to other populations. Second, almost 20% of the participants of our baseline cohort died or were not willing to participate during follow-up. Although the differences between baseline characteristics of individuals with follow-up and individuals who were lost to follow-up were numerically small (data not shown), we cannot exclude that survival bias was introduced. However, because individuals with high UAE, lower GFR, or hypertension are more likely to be lost during follow-up as a result of the associated increased morbidity and mortality, it is likely that such a bias has led to an underestimation of the true association among UAE, GFR, and development of hypertension.

Conclusion

We conclude from this prospective, community-based cohort study that UAE predicts the development of hypertension, independent of BP and other widely known risk factors for development of hypertension. Our study suggests that this is explained by the association of UAE with mild renal dysfunction. This study therefore gives epidemiologic evidence in support of the hypothesis that mild renal dysfunction may precede the onset of systemic hypertension.