Original Article: Clinical Investigation
Increase in 24-hour urine production/weight causes nocturnal polyuria due to impaired function of antidiuretic hormone in elderly men
Mitsuru Tani md, Department of Urology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan. Email: firstname.lastname@example.org
Objectives: The goals of the present study were to evaluate whether the different function of endogenous antidiuretic hormone (arginine vasopressin; AVP) results in the difference in 24-h production/weight and to make indexes of lifestyle advice for patients with nocturia due to nocturnal polyuria (NP).
Methods: A total of 205 male patients over 50 years of age were enrolled in the study. Frequency volume chart and fluid intake (time and volume) were recorded under unconditioned status. All patients submitted single voided urine sample at 06.00 hours. Urinary AVP (uAVP), sodium (uNa), creatinine (uCr), and osmolarity were measured. Patients were divided into four groups according to 24-h urine production/weight as follows: 24-h production/weight >40, 24-h production/weight: more than 30 to 40, 24-h production/weight: more than 20 to 30, 24-h production/weight: 20 or less.
Results: The data of 174 eligible patients were finally evaluated. Although there were no differences in uAVP/uCr and uNa/uCr among the groups, the nocturnal voided volume (NUV) increased with the increase in 24-h production/weight. Age, uAVP/uCr, 24-hr production/weight of more than 20 to 30, and 24-h production/weight of 20 or less were independent factors for NP. NUV did not correlate with 24-h drinking volume in any group.
Conclusion: Our data suggested that the increased 24-h urine production/weight was apparently a risk factor for NP. We attributed this phenomenon to deterioration of the function of AVP.
Nocturia decreases the quality of life (QOL) and increases mortality.1 Although nocturia has many etiologies, its two main causes are decrease in the nocturnal bladder capacity and nocturnal polyuria (NP).2 NP is closely associated with nocturia in all patients.3 Water or solute diuresis in the kidney is a major cause among various abnormal conditions leading to NP in elderly men.4 We previously reported that water diuresis mainly contributed to NP in elderly men.5
The decrease in antidiuretic hormone (arginine vasopressin; AVP) secretion at night-time or the impaired response to AVP in the renal tubules results in nocturnal water diuresis. The former seems to contribute to NP mainly, because the volume of AVP secretion at night correlated with the nocturnal urine volume (NUV) in our previous study.6 Nevertheless, there was a great variation in NUV especially in patients with low AVP levels. This phenomenon may imply that there is a difference in response to AVP in the renal tubules. The impaired response to AVP in the renal tubules may be an adverse effect of drugs such as lithium,7 electrolyte abnormalities such as hypercalcemia and hypokalemia,8 obstructive disease of the urinary tract,9 and decrease of the osmolarity gradient in the renal medulla.10 However, in patients without any obvious disease, the decrease of the osmolarity gradient in the renal medulla seems to contribute chiefly to the impaired response to AVP in the renal tubules.
Polydipsia is a disease associated with a decrease in the osmolarity gradient in the renal medulla due to increased fluid intake, and results in polyuria. Polyuria was regarded as an independent factor for nocturia in the International Continence Society (ICS) definitions.2 The definition of polyuria is 24-h urine production/body weight (24-h UP/BW) level of 40 or more. Although the impaired response to AVP commonly occurs in patients with polyuria due to increased fluid intake, it is unknown whether a difference in response to AVP exists in patients whose 24-h UP/BW is less than 40.
The most effective treatment for patients with NP and an age-related decrease in AVP secretion11 is an AVP replacement therapy, which helps restore its physiological level in these patients at night-time. However, AVP replacement therapy has adverse reactions, such as hyponatremia, headache, nausea, vomiting, and light-headedness.12 Therefore, it is important to recuperate the endogenous AVP function by following appropriate lifestyle advice.
The goals of this study were to evaluate whether the different functions of the endogenous AVP cause the differences in 24-h UP/BW and to make indexes of lifestyle advice for patients with NP.
A total of 205 male patients, aged older than 50 years, with nocturia were enrolled in this study. Patients who had past or present history of heart disease, diabetes mellitus with optional blood glucose of 200 mg/dL or more, serum creatinine (Cr) > 1.5 mg/dL, hydronephrosis, postvoid residual (PVR) > 50 mL, or active urinary tract infection, and patients habitually receiving diuretics or lithium were excluded. The purpose and method of this study were approved by our Institutional Reviewer Board and fully explained to patients, and informed consent was obtained from them.
At the first examination, blood pressure, blood count, standard chemistry panel, brain natriuretic peptide (BNP), and urinalysis were assessed routinely. PVR and hydronephrosis were checked by ultrasonography. Frequency volume chart (FVC) and fluid intake (time and volume) were recorded, and in this study NUV was defined as the total amount of urine voided between 22.00 and 06.00 hours including the first voided volume after rising from bed according to our previously reported method.6 NP was defined as NUV ≥ 0.9 mL/min × sleeping time.13 The evening drinking volume was defined as the total amount of drinking volume between 17.00 and 06.00 hours.
All patients were requested to void urine at 22.00 and 06.00 hours. A single urine sample voided at 06.00 hours was also obtained from all patients. Details of the uAVP measurements are presented in our previous article.6 Urine osmolarity, uNa, and uCr were also measured. Then, uAVP and uNa were adjusted as uAVP/uCr and uNa/uCr by uCr level to decrease the volumetric influence of urine production.
Patients were divided into four groups according to 24-h UP/BW as follows: 24-h UP/BW: 20 or less (Group A), 24-h UP/BW: more than 20–30 (Group B), 24-h UP/BW: more than 30–40 (Group C), 24-h UP/BW: more than 40 (Group D).
For statistical analyses, one-way analyses of variance and post hoc tests were used for intergroup comparisons. Spearman correlation coefficients were used to examine the relationship between urinary AVP/Cr and NUV, fluid intake, and NUV.
Logistic regression was used for analyses of putative risk factors correlating with NP. Variables with a P-value of less than 0.05 in univariate analyses were evaluated in multivariate models. A P-value of less than 0.05 was considered statistically significant. The StatView program (version 5.0) was used to conduct all statistical analyses.
After excluding 31 patients from this study because of incomplete FVC and fluid intake chart (28 patients) and blood glucose ≥ 200 (three patients), 174 patients were examined (Table 1). The numbers of patients were divided according to 24-h UP/BW as follows: Group A (n = 38), Group B (n = 69), Group C (n = 42), Group D (n = 25). There were no significant differences in blood pressure, electrolyte (Na, K, Cl, Ca), uAVP/uCr and uNa/uCr among the groups. On the other hand, there were significant differences in NUV. There were significant differences in body weight, urine osmolarity, 24-h drinking volume and evening drinking volume between higher (24-h UP/BW ≤ 30) and lower (24-h UP/BW > 30) groups.
Table 1. Characteristics of patients divided according to 24-h urine production/weight
|Age (years)*||70.0 ± 8.7||69.9 ± 7.9||73.8 ± 5.7||73.6 ± 7.1|
|Weight (kg)†||65.0 ± 12.4||63.4 ± 8.0||59.6 ± 9.5||56.5 ± 8.1|
|Systolic BP (mmHg)||135 ± 17.3||130 ± 15.2||130 ± 14.2||129 ± 14.3|
|Diastolic BP (mmHg)||74 ± 9.4||74 ± 11.5||72 ± 11.3||74 ± 11.3|
|Na (meq/L)||141 ± 2.4||141 ± 2.0||141 ± 2.6||141 ± 2.6|
|K (meq/L)||4.1 ± 0.3||4.2 ± 0.3||4.2 ± 0.4||4.2 ± 0.4|
|Cl (meq/L)||104 ± 3.0||104 ± 2.7||104 ± 3.1||103 ± 2.7|
|Ca (mg/dL)||9.2 ± 0.4||9.2 ± 0.4||9.2 ± 0.4||9.3 ± 0.4|
|BNP (pg/mL)||24.0 ± 21.0||26.8 ± 25.1||38.6 ± 28.4||40.1 ± 32.0|
|Cr (mg/dL)‡||0.8 ± 0.2||0.9 ± 0.2||0.8 ± 0.1||0.9 ± 0.1|
|uAVP/uCr (pg/mL/Cr)||33.2 ± 29.3||27.1 ± 21.3||23.5 ± 28.3||22.4 ± 27.1|
|uNa/uCr (meq/l/Cr)||4.0 ± 3.2||7.2 ± 11.5||7.8 ± 12.6||8.6 ± 14.8|
|Urine osmolarity†||593 ± 183||568 ± 147||456 ± 183||429 ± 126|
|24-h production (mL)§||1101 ± 272||1575 ± 261||2032 ± 342||2636 ± 581|
|Nocturia¶||1.8 ± 1.2||1.9 ± 1.2||2.3 ± 1.1||2.9 ± 1.8|
|Nocturnal urine volume (mL)§||383 ± 182||497 ± 198||724 ± 300||902 ± 369|
|Nocturnal polyuria index||0.35 ± 0.14||0.32 ± 0.13||0.36 ± 0.14||0.36 ± 0.16|
|24-h drinking volume (mL)†||1344 ± 509||1390 ± 500||1618 ± 514||1730 ± 728|
|Evening drinking volume (mL)†||468 ± 258||478 ± 285||614 ± 334||650 ± 452|
Independent factors influencing NP
Age, body weight, Na, Cl, K, Ca, BNP, Cr, uAVP/uCr, uNa/uCr, 24-h UP/BW, 24-h drinking volume, evening drinking volume, systolic and diastolic blood pressure were included in predictive factors (Table 2). Variables in which P-values were less than 0.05 in univariate analyses were used in multivariate analyses. Age, Cr, uAVP/uCr, 24-h UP/BW: more than 20–30, and 24-h UP/BW: 20 or less were applicable to the latter. In a multivariate logistic model, age, uAVP/uCr, 24-h UP/BW: more than 20–30 and 24-h UP/BW: 20 or less were independent predictive variables of NP.
Table 2. Multivariate analysis on associated variables correlating with nocturnal polyuria
|Weight (kg)||0.99||0.96–1.03||0.72|| || || |
|Na (meq/L)||0.9||0.98–1.001||0.13|| || || |
|Cl (meq/L)||0.99||0.98–1.001||0.28|| || || |
|K (meq/L)||1.001||099–1.02||0.98|| || || |
|Ca (mg/dL)||1.95||0.84–4.53||0.12|| || || |
|BNP||1.009||0.99–1.03||0.29|| || || |
|uNa/uCr (meq/l/Cr)||1.07||0.99–1.14||0.06|| || || |
|24-h production/weight vs. >40|
|≤40, 30<||0.58||0.14–2.43||0.45|| || || |
|24-h drinking volume (mL)||1||1.00–1.001||0.19|| || || |
|Evening drinking volume (mL)||1.001||1.00–1.002||0.09|| || || |
|Systolic BP (mmHg)||0.98||0.96–1.03||0.14|| || || |
|Diastolic BP (mmHg)||0.98||0.94–1.01||0.17|| || || |
Correlation between uAVP/uCr and NUV in each group divided according to 24-h production/weight
There was a significant correlation between uAVP/uCr and NUV except in the group whose 24-h UP/BW was more than 40 (Table 3).
Table 3. Correlation between nocturnal voided volume (NUV) and each parameter (uAVP/uCr, 24-h drinking volume and evening drinking volume)
|uAVP/uCr (pg/mL per Cr)||−0.39||0.018||−0.4||0.01||−0.26||0.04||−0.07||0.72|
|24-h drinking volume (mL)||0.23||0.14||0.004||0.97||−0.09||0.45||−0.11||0.58|
|Evening drinking volume (mL)||0.33||0.046||0.08||0.64||0.02||0.85||0.15||0.45|
Correlation between fluid intake and NUV in each group divided according to 24-h UP/BW
The evening drinking volume significantly correlated with NUV only in the group whose 24-h UP/BW was 20 or less. On the other hand, none of the groups showed a significant correlation between 24-h drinking volume and NUV (Table 3).
In the present study, 24-h UP/BW positively correlated with NUV. Although there was no significant difference in the level of secretion volume of AVP and sodium at night among the groups, the lower groups in which 24-h UP/BW was under 30 had higher urinary osmolarity than the higher groups. Therefore, this phenomenon suggests that the increase in 24-h UP/BW resulted from the impaired response to AVP in renal tubules.
Deterioration of the AVP function consists of AVP resistance in the collecting tubules and/or decrease in the osmolarity gradient in the renal medulla. Regarding the secretion of AVP, the former increases but the latter decreases.14 It might be considered that the decrease in osmolarity gradient in the renal medulla causes deterioration in the AVP functions chiefly, because there was no significant difference in the amount of the secretion volume of AVP at night among the groups.
The great fluid intake14 or the decrease in solute transport from the inner tubules to the outer tubules15 reportedly decreases the osmolarity gradient in the renal medulla. In this study, the 24-h drinking volume and evening drinking volume in the higher groups whose 24-h UP/BW was above 30 were significantly greater than those in the lower groups. Moreover, the body weight in the higher groups was significantly less than that in the lower groups. In general, the amount of water in the body was about 70% of the body weight. Therefore, the large volume of fluid intake for a person who has a small potential of keeping water may contribute to a decrease in the osmolarity gradient in the renal medulla.
It has been reported that some elderly people restricted fluid intake in order to avoid nocturia, but many elderly people in Japan took a large amount of fluid in order to prevent ischemic disease such as stroke or heart disease. As a result, urine output increased and they were annoyed by nocturia.
Nocturnal voided volume did not correlate with uAVP/Cr between the group with 24-h UP/BW and the group of more than 40. In other words, nephrogenic diabetes insipidus existed in that group. Nephrogenic diabetes insipidus is divided into congenital and secondary types.16 As the congenital type begins in infancy,16 most elderly diabetes insipidus patients are thought to be of the secondary type. Secondary diabetes insipidus may result from adverse drug reactions such as lithium,7 electrolyte abnormalities such as hypercalcemia and hypokalemia8 and obstructive uropathy.9 In this study, we excluded patients who took lithium-containing medications or suffered from obstructive uropathy. Some patients in the 24-h UP/BW > 40 group, who showed normal blood values of potassium and calcium, had NUV of more than 700 mL, although they had a high value of uAVP/uCr such as above 100 pg/dL/Cr (data not shown). Thorough investigations such as the desmopressin (DDAVP) tolerance test should be carried out for these cases.
The increase in 24-h UP/BW was an independent factor for NP in this study. Patients with nocturia due to NP should be instructed to decrease their 24-h production/weight when possible. However, it was difficult to decrease the urine output only by restriction of the fluid intake because the amount of urine output was decided by the personal status of dehydration. NUV did not correlate with the 24-h drinking volume in this study.
In clinical practice, the balance between fluid intake and output should be checked first by FVC of water intake and urine voidance in NP patients. Dontas et al. reported that minimum urine outputs of 700 and 1086 mL/day for elderly men and women were needed compared with 392 mL/day for young men because older individuals cannot concentrate urine as well as young individuals.17 Lee reported that urine output, which decreases body water, was about 50 mL/h.18 In this study, 24-h UP/BW < 30 was apparently an independent factor for NP and 24-h UP/BW of 20 or less had the potential to cause dehydration. Hence, we advise patients with nocturia due to NP to keep their 24-h UP/BW between 20 and 30 (If the body weight of these patients is 70 kg, their 24-h production should be between 1400 mL and 2100 mL).
However, it remains unclear whether the control of 24-h UP/BW is effective for patients with nocturia due to NP. Moreover, the mechanism is not fully understood, even if such treatment proves effective. Therefore, further prospective studies are necessary to verify whether the control of 24-h UP/BW is effective and to clarify the mechanism.
The increase in 24-h UP/BW is apparently an independent risk factor for NP. We considered that the impaired response to AVP caused a decrease in the osmolarity gradient in the renal medulla resulting in NP with consequent increase in 24-h UP/BW. In clinical practice, optimal 24-h UP/BW is between 20 and 30 for patients with nocturia due to NP. Further prospective studies are necessary to verify whether the control of 24-h UP/BW is safe and effective for patients with high 24-h UP/BW who with nocturia due to NP.