Introduction

Nocturia is common and can negatively affect quality of life, especially in the elderly population. Because nocturia is thought to be caused mainly by urinary retention and voiding disorders, such as benign prostatic hyperplasia (BPH) and overactive bladder (OAB), urologists often assess patients with BPH or OAB with the International Prostate Symptom Score. In patients with nocturia due to BPH or OAB, α-blockers or PDE5 inhibitors are effective at improving lower urinary tract symptoms. Nocturia due to impaired concentration of the urine by the renal tubules is commonly observed in clinical practice, and such patients should avoid water intake for a few hours before bedtime or take loop diuretics during the daytime.

When we examine patients with cardiovascular diseases such as hypertension and heart failure, we sometimes hear complaints of nocturia. It is estimated that 43 million people are affected by hypertension, and relatively higher percentages of Japanese hypertensive patients have salt sensitivity and high-salt intake levels [1]. Therefore, the reduction of salt intake and potassium intake are considered very important lifestyle factors to address in patients with hypertension [2, 3]. Potassium intake promotes natriuresis, which results in antihypertensive effects [4]. Heart failure is a common disease among the elderly population; it can lead to death and decreased patient quality of life and ability to perform activities of daily living, with repeated episodes of hospitalization [3]. One of the symptoms of heart failure is nocturia, and in daily clinical practice, we often encounter patients with heart failure complaining of nocturia. In patients with heart failure and hypertension, nocturnal polyuria due to increased nocturnal urine production may also lead to nocturia. In the 2nd edition of the Clinical Guidelines for Nocturia published jointly by the Japanese Continence Society and the Japanese Urological Association in May 2020, the systematic review and guidelines focused particularly on increased nocturia in patients with cardiovascular diseases [5]. As we considered the content to be important not only for urologists, who often treat nocturia, but also for internal medicine physicians, we summarized the available data in a systematic review.

Systematic review of hypertension and nocturia

Using nocturia and hypertension as keywords, PubMed was searched for articles up to March 2019, and 175 articles were retrieved. Two of these articles were reviews of nocturia, 3 were reviews of the association between nocturia and hypertension, 1 was a longitudinal study, 31 were cross-sectional studies, and 1 was a case-control study. Of the 31 cross-sectional studies, 27 showed that there was an association between nocturia and hypertension.

A review of factors associated with nocturia has already been published [2]. That review article identified 85 articles; excluded 3 systematic reviews, 2 topic reviews, and 28 topic reviews; and ultimately included 52 articles in the analysis. Hypertension was significantly associated with nocturia in both men and women, and approximately twice as many individuals in the group with nocturia had hypertension than in the group without nocturia [6]. In 2020, an additional systematic review and meta-analysis reported that hypertension was associated with a 1.2- to 1.3-fold higher risk of nocturia based on 25 articles that met the criteria for inclusion [7].

A cross-sectional study of 8284 people aged ≥40 years in the general population showed that hypertension was associated with a two-fold higher risk of urination during sleep in women but not in men [8]. In the OASIS project, a multicenter study in Japan, hypertension was shown to be a risk factor for overactive bladder in women with lifestyle-related diseases [9]. Furthermore, in a study of 728 Japanese patients with lower urinary tract symptoms, hypertension was shown to be significantly associated with nocturia in multivariate analysis (odds ratio 9.79, 95% CI 6.53–14.9, p < 0.001) [10]. In addition, many reports have suggested that nocturia is associated with hypertension in the general population [11,12,13,14,15,16,17,18,19,20,21]. Blood pressure has also been shown to be significantly higher in elderly people with nocturia than in elderly people without nocturia [18]. Interestingly, a cross-sectional study using the Nagahama cohort showed an association between nocturnal hypertension and nocturia [22].

On the other hand, few reports have addressed the relationship between nocturia and hypertension in patients with any disease. One report examined factors associated with nocturia using a questionnaire survey of 2,934 elderly male patients attending 21 general clinics and found that hypertension was significantly associated with nocturia [23]. Nocturia has also been found to be significantly associated with hypertension in patients with diabetes and sleep apnea syndrome [24, 25], but nocturia was not associated with hypertension in 51 patients with a history of cerebral infarction [26]. In another study, 65% of the patients had persistent nocturia, which, unlike transient nocturia, was significantly associated with hypertension in 1240 male patients attending follow-up with urologists [27].

In a longitudinal study of 2447 men aged 40–79 years, nocturia was not associated with the development of hypertension but was associated with the development of coronary artery disease in men younger than 60 years of age over a mean observational period of 17.1 years [28]. As described above, complications of hypertension should be taken into consideration in cases of nocturia, but the influence of nocturia on the development of hypertension is still unclear.

Pathophysiology of hypertension and nocturia

An important mechanism causing nocturnal polyuria in patients with hypertension is sodium retention and the consequent increased urine production. Prof. Guyton’s concept of the pressure-natriuresis curve, which is well known in physiology, states that urinary sodium excretion increases rapidly when systolic blood pressure increases above a threshold of 110–120 mmHg and that systolic blood pressure normalizes when sufficient natriuresis has been achieved (Fig. 1) [29]. In the case of salt-insensitive hypertension, the threshold for the initiation of natriuresis is 140 mmHg, but urinary sodium excretion can result from a slight increase in blood pressure during the daytime. On the other hand, in the case of salt-sensitive hypertension, blood pressure must increase considerably to achieve urinary sodium excretion even though the threshold is the same; even in patients with much higher blood pressure levels than those in patients with salt-insensitive hypertension, salt excretion during the daytime is insufficient, forcing the patients to excrete salt at night. To excrete salt, urine must be produced, and it is easy to understand how nocturnal polyuria leads to nocturia.

Fig. 1
figure 1

Guyton’s pressure-diuresis curve and nocturnal natriuresis. Modified from Ref. [23]

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In a clinical study, patients with salt-sensitive hypertension who consumed a high-salt diet (12–15 g/day) for a week had an extremely large increase in their nocturnal blood pressure compared to those on a low-salt diet (1–3 g/day) [30]. When patients with chronic kidney disease, who are representative of the population with salt-sensitive hypertension due to impaired salt excretion, underwent 24-h ambulatory blood pressure monitoring, most were found to have nondipping early morning hypertension and nocturnal hypertension [31]. When thiazide diuretics were taken in the morning, patients with dipping early morning hypertension and no nocturnal hypertension did not experience a significant reduction in their daytime or nighttime blood pressure values, whereas the those with dipping early morning hypertension and nocturnal hypertension had a stronger antihypertensive effect at night, when thiazide diuretics were considered to be ineffective [32]. This may be because thiazide diuretics result in the excretion of sodium during the daytime, obviating the need for nocturnal sodium excretion, which explains the lack of increase in blood pressure.

A clinical investigation estimating the daily salt intake and the frequency and volume of daytime and nighttime urination in 728 patients with lower urinary tract symptoms at a urology department of a university hospital in Japan showed that excessive salt intake is associated with nocturnal polyuria and nocturia [10]. In that study, excessive salt intake, male sex, renal dysfunction, and hypertension were independent risk factors for nocturia, which strongly supports the existence of a relationship between excessive salt intake and nocturnal hypertension. In addition, Cho et al [33]. reported that when thiazide diuretics were administered to male patients with nocturia who had already been treated with alpha-blockers, there was no increase in urinary frequency or volume during the daytime, when the diuretics were effective; however, urinary frequency and volume decreased significantly at night. These results suggest that sodium excretion induced by thiazide diuretics is effective for the treatment of nocturnal polyuria and urinary frequency, and this is considered a new therapeutic approach to nocturia. Although loop diuretics are often used as a treatment for nocturia, they are not effective in patients with salt-sensitive hypertension because loop diuretics are mainly water diuretics rather than natriuretics, and sufficient sodium excretion cannot be achieved with loop diuretics. Thiazide diuretics, rather than loop diuretics, should be considered for the treatment of nocturia in patients with nocturnal hypertension rather than early morning hypertension due to aging, renal dysfunction (excretion disorders), obesity, diabetes mellitus, postmenopausal status, or genetics (hypersodium reabsorption).

Systematic review of heart failure and nocturia

Using nocturia and heart failure as keywords, PubMed was searched for articles up to March 2019, and 54 articles were retrieved. The articles included six reviews on factors associated with nocturia, one review on the association between heart failure and sleep disturbances, four cross-sectional studies, and one case-control study.

The previous review described above showed that heart failure was not significantly associated with nocturia in either men or women [6]. However, several other reports also addressed the association between nocturia and heart failure. One report prospectively analyzed the clinical data from 452 consecutive patients with acute dyspnea in the emergency department, and 217 patients with dyspnea due to acute heart failure had an elevated risk of nocturia (OR 2.4; 95% CI 1.6–3.7) [34]. In a cross-sectional study of 173 patients with chronic heart failure, 87 patients urinated 1–2 times during the night, and 56 patients urinated 3 or more times during the night, resulting in sleep disturbances [35]. Among 53 COPD patients aged ≥65 years, 8 patients met the criteria for heart failure (NT-pro BNP ≥ 1200 pg/ml), and the proportion of patients with nocturia was higher in those patients than in patients with NT-pro BNP levels <1200 pg/ml [36]. In a study of 74 patients hospitalized for congestive heart failure [37], 39 patients with nocturia had significantly higher BNP levels than the group without nocturia, indicating that nocturia may be associated with the severity of heart failure.

As described above, inconsistent results have been reported with regard to the relationship between nocturia and heart failure in several papers. Although the pathogenesis of heart failure is diverse and the diagnosis is complicated, the relationship between nocturia and heart failure has not been sufficiently clarified, and further studies are needed.

Pathophysiology of heart failure and nocturia

An important mechanism of nocturnal polyuria in heart failure patients is increased urine production due to water diuresis as a response to water retention. This is very different from nocturnal polyuria in patients with salt-sensitive hypertension, where the mechanism involves increased urine production due to sodium diuresis. Recently, heart failure has been classified based on the ejection fraction as heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Although HFpEF may be related to water retention, the mechanism underlying HFpEF is still unclear. Therefore, we present the mechanisms underlying HFrEF in Fig. 2. When cardiac output decreases due to a decrease in cardiac contractility, venous return (circulating fluid volume) increases to compensate for the preload. However, when venous return from the periphery increases due to being in a supine position at night, this adaptation fails, and excessive blood flow to the center (central shift) causes orthopnea [38]. Atrial and ventricular stress increased by that central shift leads to the production of members of the natriuretic peptide family, such as ANP and BNP, and nocturnal urine production is increased. As shown in Fig. 2, diuresis in heart failure patients is considered an adaptive phenomenon to prevent clinical deterioration. This mechanism involving nocturnal polyuria and increased urinary frequency in heart failure patients to resolve water retention differ from the nocturnal polyuria and urinary frequency in patients with hypertension to resolve excessive sodium retention. As the goal of treatment is to relieve water retention, nocturnal polyuria due to heart failure is most effectively controlled by limiting water intake while awake and taking loop diuretics, while thiazide antihypertensive diuretics are ineffective because they do not have a significant effect on water retention. The prolonged use of loop diuretics is known to increase the activity of Na-Cl cotransporters due to the sensing of decreased chlorine iron delivery in the macula densa, resulting in increased sodium reabsorption and prolonged edema. As thiazide diuretics are often used to suppress sodium reabsorption, they are thought to have little effect on nocturnal polyuria, which involves diuresis due to increased venous return. Recently, sodium glucose cotransporter 2 (SGLT2) inhibitors have been used for the treatment of heart failure. Clinical studies have shown that SGLT2 inhibitors not only decrease venous return through diuresis but also increase sodium excretion [39]. This suggests that SGLT2 inhibitors may be effective not only for reducing venous return in patients with heart failure but also for reducing salt retention in patients with hypertension.

Fig. 2
figure 2

Adaptation, failure and promotion in heart failure with reduced ejection fraction. EF ejection fraction, RAS renin angiotensin system, SNS sympathetic nervous system

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The Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure published jointly by the Japanese Circulation Society (JCS) and the Japanese Heart Failure Society (JHFS) in 2017 [40] aimed to improve diagnostic procedures by creating a diagnostic flowchart for chronic heart failure, but it is often difficult for noncardiologists to reach a definitive diagnosis because heart failure is based on a comprehensive assessment of the symptoms and examination results. To determine whether a patient with nocturnal polyuria or nocturia has heart failure, the BNP or NTpro-BNP levels can be used as a reference when symptoms, such as shortness of breath and edema, are present. According to the JCS 2017/JHFS 2017 guidelines, a BNP level <40 pg/ml and a NTpro-BNP level <125 pg/ml are unlikely to indicate heart failure, whereas a BNP level of 40–100 pg/ml and a NTpro-BNP level of 125–400 pg/ml may indicate mild heart failure, and the patient should be monitored closely. If the symptoms are atypical or a diagnosis cannot be made, referral to a specialist should be considered. A BNP level ≥100 pg/ml and a NTpro-BNP level ≥400 mg/ml indicate the possibility of treatable heart failure, and referral to a specialist is recommended. A BNP level ≥200 pg/ml and a NTpro-BNP level ≥900 mg/ml indicate the possibility of heart failure that needs treatment. If a diagnosis cannot be reached, referral to a specialist should be considered.

Systematic review of coronary artery disease and nocturia

Using nocturia and coronary artery disease or coronary heart disease as keywords, PubMed was searched for articles up to March 2019, and 10 and 20 articles were retrieved, respectively. A few studies on the association between nocturia and coronary artery disease have been published. The survival rate at 12 years of follow-up in 456 subjects was significantly lower in patients with nocturia than in patients without nocturia, and the interaction between nocturia and history of coronary artery disease was significant (p < 0.0001), with an interaction variable hazard ratio of 2.16 (95% CI 1.01–4.61) [41]. Furthermore, the survival rates in patients with nocturia (n = 54) and those without nocturia (n = 65) were 44% and 66%, respectively (p = 0.0201), and nocturia was an independent predictor of life expectancy in 70-year-old patients with a history of coronary heart disease. A report of factors associated with nocturia based on a questionnaire administered to 6000 randomly selected Finnish residents aged 18–79 years showed that nocturia (urinating more than twice during the night) was associated with a history of coronary artery disease in women [42].

However, in patients younger than 60 years of age, nocturia was associated with coronary heart disease, but the association did not remain significant after adjusting for age, BMI, and the use of urological medications in a retrospective study of 2447 men aged 40–79 years (mean follow-up 17.1 years) with or without moderate nocturia, which was defined as awakening to urinate two or more times during the night. In patients >60 years of age, nocturia was associated with mortality independent of previous risk factors and coronary heart disease, but coronary heart disease was not associated with nocturia [28]. As described above, although few reports have been published on the relationship between nocturia and coronary heart disease, coronary heart disease may need to be taken into account in patients complaining of nocturia.

Pathophysiology underlying the relationship between coronary artery disease and nocturia

The pathophysiology underlying the relationship between coronary artery disease and nocturia differs greatly from that underlying the relationship between hypertension and heart failure. Coronary artery disease is the result of atherosclerosis of the coronary arteries, and atherosclerosis is a vascular remodeling process that involves endothelial dysfunction, intimal thickening due to smooth muscle cell proliferation, and plaque formation and disruption [43]. Coronary artery disease is a lifestyle-related disease that develops in a group of patients with so-called coronary risk factors, such as hypertension, diabetes, dyslipidemia, smoking, and obesity. Recently, BPH [44] and OAB [45] were reported to be lifestyle-related diseases that develop as a result of metabolic syndrome.

Various cytokines and growth factors are involved in atherosclerosis, including the renin-angiotensin (RA) system [46, 47]. Angiotensin-converting enzyme (ACE) inhibitors are useful for secondary prevention after myocardial infarction and are recommended as class I agents in various guidelines. In human coronary arteries, ACE is strongly expressed on macrophages around plaques [48], and angiotensin II type 1 (AT1) receptors are expressed on intimal smooth muscle cells around plaques [49]. In vivo autoradiography and immunohistochemistry of ACE, in vivo autoradiography of angiotensin II, and AT1 receptor immunostaining in human prostate tissue have shown that in compared with normal prostates, prostate tissue in patients with PBH have two-fold higher ACE protein expression levels, 10-fold higher ACE activity levels [50], and three-fold higher AT1 receptor expression level in prostate smooth muscle cells and angiotensin II levels [51]. Based on these pathological investigations, similar to in human coronary arteries, the activated RA system in human prostate tissue may induce smooth muscle cell proliferation, leading to prostate hypertrophy.

As described above, coronary artery disease and BPH are presumed to not be directly associated, but they share a common basis in atherosclerosis and are lifestyle-related diseases.

Clinical perspective

Although nocturia is a condition that significantly impairs quality of life, physicians and cardiologists do not usually pay much attention to it in general practice. A systematic review showed an association between nocturia and lifestyle-related diseases, such as hypertension, heart failure, and coronary artery disease, suggesting that physicians need to pay close attention to nocturia or nocturnal polyuria. First, we should evaluate urinary retention and voiding disorders to diagnose BPH or OAB based on the International Prostate Symptom Score. Furthermore, natriuresis and water diuresis are the main mechanisms underlying increased nocturia in patients with hypertension and heart failure, respectively, and thiazide antihypertensive diuretics and loop diuretics are the appropriate therapeutic agents (Fig. 3). However, coronary artery disease is not a direct risk factor for nocturia but rather the result of a common cause, atherosclerosis, so it is necessary to pay attention to the appearance of nocturia when following patients with coronary artery disease.

Fig. 3
figure 3

The mechanisms underlying nocturia in patients with cardiovascular diseases and hypertension. Mets metabolic syndrome, CAD coronary artery disease, BPH benign prostate hyperplasia, OAB overactive bladder

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