This study demonstrated a significant positive association between the measured depression symptoms and moderately increased albuminuria. However, the association weakened after adjusting for age and sex, and after multivariable adjustment the significant association disappeared. Therefore, the unadjusted correlation between depression symptoms and albuminuria in the study population seemed to be explained by other factors causing possible inflammation, like increased CV risk and other comorbidities.
A positive association between albuminuria and depressive symptoms/depressive episodes has been published by Martens et al 12. This study has also a cross sectional design, however with fewer participants than ours. As mentioned by the authors, almost 1/3 had diabetes type 2, compared to 16% in our study, and although adjustment of this comorbidity in both studies, the population from Netherlands might have a higher cardiovascular (CV) risk profile. Additionally, the studies differed in methods regarding classification of depressive symptoms (PHQ-9 versus HADS), and Martens et al. also included a clinical interview (MINI) to assess the presence of minor or major depressive episodes, which gives a more valid classification of depressive episodes. HADS is not a diagnostic instrument for clinical diagnoses, but it identifies seven depressive symptoms. A literature review, which includes 31 studies, concluded that the HADS holds good properties for depression in patient populations in primary care and hospital settings 15. Even high scores of HADS-D do not give a depression diagnosis, but HADS has been used in several studies, including HUNT studies 16,17. Various cut-off levels have been reported from various study populations, and studies comparing HADS with «gold standard» or reference standard diagnostic interviews for depression disorder have disclosed reasonable validity 18,19. The Norwegian version of HADS is a relatively well validated screening instrument for anhedonia and psychological distress 20,21.
Depression and stress related symptoms may be associated with a chronic, low-grade inflammation response, and studies have shown association between depression and activation of cell-mediated immunity as well as increased oxidative and nitrosative stress 22. Several factors increase the risk for development of depression whilst they also are associated with systemic inflammation; psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency 22. Some of these factors are also associated with albuminuria, like physical inactivity 23, obesity 24,25 and smoking 26,27, and were included as confounders in our analyses, and might have been stronger associated with albuminuria than depression symptoms.
The cerebral small vessel disease, defined as a disease of the small blood vessels in the brain, and a frequent cause of stroke and dementia, is also hypothesized to lead to depression (the vascular depression hypothesis) through disruption of neuronal circuits involved in mood regulation 28,29. Although we recently published the results of a positive association between vascular dementia and low-grade albuminuria 30 and have found significant association between lacunar stroke and albuminuria 31 in the same HUNT-material, we could not support the vascular depression hypothesis by our results. However, the results may reflect the limitation of HADS in measurement of depression more than the true association between depression and vascular endothelial dysfunction.
There are several strengths of this study. The population-based approach and the high attendance rate make selection bias less likely. The response rate in the albuminuria screening was especially high in the elderly and those with diabetes and treated hypertension 32. Another strength was that albuminuria analyses were performed in fresh urine samples without long-term storing, in contrast to other studies 33. Several studies conclude that measuring ACR is a specific and sensitive alternative to twenty-four-hour urine collection in population-based albuminuria screenings 34,35.
One of the most important limitations is the self-reported symptoms of depression, which always may lead to misclassification. As the HADS questionnaire does not mirror somatic depressive symptoms, cases with predominantly somatic depressive, i.e. biologically based symptoms, as weight loss, fatigue and insomnia, might be undetected. However, these symptoms overlap with several other morbidities, which might be associated with albuminuria, thus somewhat underestimating than overestimating our results. There is probably considerable variability of inflammation within the depressed population, and there are studies that find subtypes of depression which are more inflammation-related 36. On the other hand, HADS has shown in other studies association with inflammation-variables, as CRP 37. Further, we had no information about medical treatment of depression, where treatment by tricyclic antidepressant could increase CV risk 38 in contrast to selective serotonin reuptake inhibitors which are associated with reduced CV risk 39. Another limitation is the lack of other inflammatory markers. The HUNT study includes a large population and questions about several diseases, and because of limited resources specific inflammation- or biological parameters for most diseases were not included. Neither we have information about all comorbidities in this epidemiological study since comorbidities are very heterogeneous. We therefore adjust for risk factors and comorbidities most correlated with albuminuria and depression.
Further, the information about use of other medication, which could have influenced albuminuria levels, was lacking, i.e. use of among others angiotensin converting enzyme (ACE) inhibitors and angiotensin II blockers (ATB). However, at the time of HUNT 2, the use of ACE inhibitors and ATB in Norway were still low. Another limitation includes the diagnosis of urinary tract infection (UTI). Those who reported UTI in the previous week were excluded from the analyses, but we were not able to adjust for asymptomatic UTI. This could contribute to a non-differential misclassification that might further weaken the associations found. The cross-sectional design limits the possibility for discovering cause-effect relationships.
Although the association between symptoms of mood disorders and albuminuria was non-significant after multi adjustment in this study, there was a significant increased prevalence of albuminuria in the depressive symptoms sample compared to the non-depressive. Intervention in albuminuria positive individuals with diabetes or hypertensive are recommended and include more aggressive treatment of CV risk factors like blood pressure, smoking, hyperlipidemia and overweight 40,41. So far, there are no recommendations of albuminuria screening in otherwise healthy people, although small studies have found reduction of CVD by intervention with ACE inhibition 42. Individuals with depression and elevated peripheral inflammatory markers, included albuminuria might have benefit of anti-inflammatory agents, such as acetyl-salicylic acid (ASA), statins, ACE inhibitors and ATB to improve the treatment of depression and other mood disorders, leading to reduction of disability, even though there is much more research to be carried out here.
In conclusion, the positive and significant association between moderately increased albuminuria and depressive symptoms found in unadjusted analyses weakened and disappeared after adjustments, indicating that albuminuria is stronger associated with age, other comorbidities, and CV risk factors. Another screening or diagnostic tool for depressive symptoms should also be considered in this case.