The pathophysiology of nocturia, defined as clinically significant at ≥2 nighttime voids, and its primary etiology, nocturnal polyuria (NP), defined as nocturnal urine volume ≥33% of the 24-hour voided volume, involves a variety of factors, including urological, nephrological, hormonal, sleep, and cardiovascular factors.¹ Of these, the dysregulation of hormones involved in water homeostasis plays a strong role, especially with increasing age. For example, the nighttime physiological increase in antidiuretic hormone has been noted to be absent in elderly individuals.² Changes in hormone levels with aging may be in part due to increasing oxidative stress and mitochondrial dysfunction, which triggers specific pathways impacting a variety of proteins that can serve as biomarkers.³ While natriuretic peptides, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), affect water homeostasis, they have not been studied in the context of nocturia and NP, especially in the aging patient population. We evaluated the impact of aging on urine natriuretic peptides in nocturia and NP.

For the study, 51 patients aged ≥18 years were recruited from 2019 to 2021 to complete 24-hour bladder diaries for assessment of nocturia and NP, with exclusion criteria including factors that may impact nocturia (benign prostatic hyperplasia, congestive heart failure, diabetes mellitus, alcohol use, diuretic use, etc). Urine samples from the patients were collected and analyzed for levels of NT-proANP, NT-proBNP, and NT-proCNP, which are the inactive terminal regions of the hormones that are secreted in equimolar ratios to the active regions and have longer half-lives. Since morning plasma levels would correlate to the physiological state of the patient during the time of testing, we hoped that the urine metabolites would correlate to the physiological state of the patient a few hours before the testing (during the sleep period). Patients were stratified by status of nocturia/NP and age subgroups for analysis.

No baseline differences (age, sex distribution, BMI, blood pressures, serum and urine creatinine) between patients with and without nocturia or NP were seen. Compared to patients without nocturia, those with nocturia had higher urine NT-proANP and NT-proBNP levels but showed no differences in NT-proCNP; similar trends were seen for NP. For both patients with nocturia and NP, the ≥65 years subgroup had about 2–3 times higher urine NT-proANP and NT-proBNP than the <65 years subgroup. Similarly, age positively correlated with urine NT-proANP and NT-proBNP for patients with nocturia and NP.

Overall, our work suggests that ANP and BNP may be playing a role in the pathophysiology of age-related nocturia and NP. An increase in these natriuretic peptides would lead to increased diuresis that may in part manifest as greater nighttime voiding. On the other hand, CNP, while also involved in natriuresis, has other functions in bone growth, neuronal development, and reproduction, and therefore may be more tightly controlled by homeostatic mechanisms.⁴ Age-related increases noted in ANP and BNP for patients that had nocturia and NP may be explained by other expected age-related changes such as left/right ventricular hypertrophy, right ventricular dysfunction from pulmonary disease, endocrine dysfunction, and increased inflammation.⁵ In particular, left ventricular hypertrophy due to increasing blood pressures with aging would most directly cause greater synthesis and release of natriuretic peptides, which could help explain their association to nocturia.^6,7 By using extensive exclusion criteria, we hoped to minimize confounding by external factors and isolate the relationship between natriuretic peptides and age-related nocturia and NP; however, this led to a smaller sample size. To further support the relationships seen, larger sample multicenter studies should be done to assess how natriuretic peptides may be impacting lower urinary tract symptoms.

This study opens the possibility of using the levels of natriuretic peptides to evaluate nocturia and potentially explaining an important contributing factor to its pathophysiology. The significance of understanding this underlying pathophysiology is that it gives the opportunity to study and develop treatment pathways targeted to specific age demographics that can help improve nocturia. Since nocturia is one the most prevalent lower urinary tract symptoms that impact quality of life,¹ we urge further research to understand its underlying pathophysiology.