NDT Advance Access originally published online on April 20, 2006
Nephrology Dialysis Transplantation 2006 21(8):2172-2177; doi:10.1093/ndt/gfl165
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Clinical Nephrology
Polynocturia in chronic kidney disease is related to natriuresis rather than to water diuresis
Department of Internal Medicine and Pathophysiology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
Correspondence and offprint requests to: Michio Fukuda, MD, Department of Internal Medicine and Pathophysiology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan. Email: momoca{at}sage.ocn.ne.jp
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Abstract |
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Background. Nocturnal polyuria has been well known in renal insufficiency. Recently, we found that as renal function deteriorated in chronic kidney disease (CKD), natriuresis was enhanced during the night with nocturnal blood pressure elevation. In the present study, we investigated whether nocturnal polyuria in CKD was due to the inability to concentrate urine, as previously proposed, or based on osmotic diuresis mainly by natriuresis.
Methods. In 27 CKD patients, circadian rhythms of urinary sodium, potassium, urea and osmolar excretion rates (UNaV, UKV, UureaV, UosmV) as well as of urinary volume (V) and free-water clearance (CH2O) were estimated during both daytime (6:00 to 21:00) and nighttime (21:00 to 6:00). Then, the night/day ratios of these parameters were analysed in relation to creatinine clearance (Ccr) as a marker of glomerular filtration rate.
Results. Ccr had significantly negative relationships with night/day ratios of V (R = –0.69; P < 0.0001), UosmV (R = –0.54; P = 0.004) and UNaV (R = –0.63; P = 0.0005), but no correlation with night/day ratios of CH2O (R = –0.33; P = 0.1), UKV (R = –0.29; P = 0.1) or UureaV (R = –0.31; P = 0.1). Linear and multiple regression analysis identified nocturnal natriuresis rather than urea excretion as an independent determinant of nocturia.
Conclusion. As renal function deteriorated, nocturnal polyuria was seen, being consistent with classical recognition. Furthermore, this increase in nocturnal urine volume seemed related to osmotic diuresis mainly by natriuresis rather than to water diuresis or urea excretion.
Keywords: blood pressure; circadian rhythm; natriuresis; nocturnal polyuria; renal function
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Introduction |
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It has been empirically thought that the capability to concentrate urine is impaired as renal function deteriorates [1,2], causing nocturnal polyuria as a precocious and ubiquitous symptom of chronic kidney disease (CKD) [2,3]. On the other hand, we have recently reported that urinary sodium excretion during the night is enhanced as renal function deteriorates [4] and as the circadian rhythm of blood pressure (BP) becomes non-dipper type [4–6], suggesting that nocturnal polyuria may be based on pressure-natriuresis during the night. Therefore, we examined whether nocturnal polyuria is due to free-water or osmotic diuresis, and whether osmotic diuresis is based on urea excretion or natriuresis during the night.
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Patients and methods |
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Patients and study protocol
Twenty-seven patients with CKD (12 men and 15 women; aged 20–80 years; mean age 53 ± 4 years; body weight 56.3 ± 3.0 kg, body mass index 21.8 ± 0.8 kg/m2) were studied in Nagoya City University Hospital during hospitalization. CKD was defined as the presence of kidney damage or decreased glomerular filtration rate (<60 ml/min/1.73 m2) for three months or more according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) CKD criteria [7]. Their histological diagnoses were as follows: IgA nephropathy in seven, nephrosclerosis in eight, membranous nephropathy in one, focal segmental glomerulosclerosis in three, lupus nephritis in four, myeloperoxidase antineutrophil cytoplasmic antibody-related vasculitis in three and amyloidosis in one. No patient with diabetic nephropathy or massive oedematous state was included. Patients under usage of antihypertensive agents or diuretics were excluded. All participants were consecutively enrolled after giving informed consent. Patients ate a relatively low-sodium diet containing approximately 8 g/day of NaCl for at least 4 weeks, and were allowed usual daily life activity and water intake, except that they were asked to get up at 6:00 and to go to sleep at 21:00. Ambulatory BP for 24 h was monitored every 30 min, non-invasively with a validated automatic device (model ES-H531, Terumo, Tokyo, Japan). Urinary samples were collected for both daytime (6:00–21:00) and nighttime (21:00–6:00) to estimate circadian rhythms of urinary sodium, potassium, creatinine, urea and total osmolar excretion rates (UNaV, UKV, UcrV, UUreaV, UosmV) as well as of urinary volume (V), osmolar clearance (Cosm) and free-water clearance (CH2O). On the other hand, blood samples were collected only once during the 24 h in the early morning and under fasting conditions. Then the same plasma values were used for both day and night to calculate the osmolar and free-water clearances of day and night, because changes in plasma composition between day and night are probably small and would not alter their calculations very significantly. CH2O was calculated as V – Cosm from its definition. Plasma and urine osmolality (mOsm/kgH2O) was estimated as 2 x (Na + K) + glucose +urea [1,8], where Na (mmol/l), K (mmol/l), glucose (mmol/l) and urea (mmol/l) are concentrations measured in serum or urine. Mean arterial pressure (MAP) was calculated as diastolic BP plus one-third of the pulse BP. Daytime BP was calculated as the average of the 30 readings between 6:00 and 21:00, whereas nighttime BP was the average of the remaining 18 readings. Then, the night/day ratios of MAP, V, UNaV, UKV, UureaV, UosmV and CH2O were analysed in relation to 24 h creatinine clearance (Ccr) as a marker of the glomerular filtration rate. Since CH2O frequently had negative values, the day–night difference was exceptionally evaluated in addition to its night/day ratio for CH2O. Kidney function of the participants (n = 27) was defined by the K/DOQI CKD classification [7]: I (Ccr > 90 ml/min/1.73 m2; n = 9), II (60 < Ccr < 89 ml/min/1.73 m2; n = 6), III (30 < Ccr < 59 ml/min/1.73 m2; n = 3), IV (16 < Ccr < 29 ml/min/1.73 m2; n = 2), and V (Ccr < 15 ml/min/1.73 m2; n = 7). Participants were divided into three groups with equal number of patients in each, to compare parameters according to kidney function: group A (normal kidney function; CKD stage I; n = 9), group B (mild-to-moderate reduction in Ccr; CKD stages II and III; n = 9), and group C (severe reduction in Ccr; CKD stages IV and V; n = 9).
Statistical analysis
Results are expressed as the mean ± SEM. The significance of differences among the three groups according to CKD stages was tested by one-way ANOVA, followed by Fisher's protected least significant difference post hoc test (PLSD test) to compare between groups A and C. The significance in each parameter for day–night difference (nocturnal reduction) and CKD stage difference among the three groups in addition to the presence of their interaction (alternating action) was tested based on two-way ANOVA with repeated measures. The correlations among Ccr and night/day ratios of MAP, V, UNaV, UKV, UureaV, UosmV and CH2O were obtained by the method of least-squares. Multiple regression analysis was performed to identify independent variables to determine the night/day ratio of V, as a marker of polynocturia. P-values of 0.05 or less were considered statistically significant.
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Results |
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Demographics of participants are summarized in Table 1. Average values in all participants (n = 27) of serum creatinine and Ccr were 2.0 ± 0.4 mg/dl (173 ± 33 µmol/l) and 67 ± 9 ml/min/1.73 m2, respectively. Average proteinuria was 1.7 ± 0.4 g/day. While age, plasma osmolality (Posm) and serum creatinine were higher in group C than in group A, there were no differences in male/female distribution, body weight, body mass index, proteinuria, systolic BP, diastolic BP or daily urine volume among the three groups. Ccr and Cosm were greater in group A, while CH2O was greater in group C.
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The day–night values of main parameters as well as the significance of the nocturnal reductions, stage difference among the three groups and their interaction with the nocturnal reductions and stages were summarized in Table 2. There was a significant nocturnal reduction from day to night only in the heart rate. The heart rate became higher as the renal function deteriorated from group A to C (P = 0.049). As already seen in Table 1, there were no differences in BP or urinary volume among the three groups besides UNaV. On the other hand, UKV (P = 0.03), UcrV (P = 0.003) and UureaV (P = 0.005) were smaller as renal function deteriorated. UosmV (P = 0.06) also tended to be smaller with renal dysfunction. CH2O (P = 0.02) was greater as renal function deteriorated. Day–night differences in MAP (P = 0.0002), V (P = 0.0002), UNaV (P = 0.001) and UosmV (P = 0.01) were significantly different among the three groups, but not the heart rate (P = 0.2), UKV (P = 0.3), UcrV (P = 0.9), UureaV (P = 0.2) or CH2O (P = 0.2).
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The night/day ratios of both V (R = –0.69; P < 0.0001) and UosmV (R = –0.54; P = 0.004) had significantly negative relationships with Ccr (ml/min/1.73 m2) as shown in Figure 1. However, the night/day ratio of CH2O (R = –0.33, P = 0.1) or the day–night difference in CH2O (R = –0.28, P = 0.2) was not correlated with Ccr. Among major solutes constituting urinary osmolality, only the night/day ratio of UNaV (R = –0.63; P = 0.0005) had a significantly negative relationship with Ccr, while the night/day ratios of UKV (R = –0.29; P = 0.1) or UureaV (R = –0.31; P = 0.1) did not (Figure 2). Similarly, compared with patients with normal Ccr (group A; Ccr > 90), those with lower Ccr (group C; Ccr < 30) had significantly higher night/day ratios of MAP (1.1 ± 0.03 in group C vs 0.9 ± 0.02 in group A; P < 0.0001), urine volume (1.6 ± 0.1 vs 0.8 ± 0.1; P < 0.0001), UNaV (1.8 ± 0.2 vs 0.7 ± 0.1; P = 0.0007), and UosmV (1.4 ± 0.1 vs 0.8 ± 0.1; P = 0.006), nocturnal reductions of which were all significantly affected by stages as already seen in Table 2.
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The night/day ratio of MAP (R = –0.64, P = 0.0004) was negatively correlated with Ccr, although absolute levels of 24 h MAP (R = –0.12, P = 0.6) were not. The night/day ratio of MAP also showed positive relationships with night/day ratios of V (R = 0.52, P = 0.006), UNaV (R = 0.46, P = 0.02) and UosmV (R = 0.40, P = 0.04), but not with night/day ratios of UKV (P = 0.6), UureaV (P = 0.2) or UcrV (P = 0.98).
The night/day ratio of V, as a marker of nocturnal polyuria, showed a positive relationship with the night/day ratio of UosmV (R = 0.82; P < 0.0001), but not with the night/day ratio of CH2O (R = 0.25; P = 0.2) as shown in Figure 3. The day–night difference in CH2O (R = 0.34; P = 0.1) was not correlated with the night/day ratio of V, either. Since the night/day ratio of UosmV was correlated with night/day ratios of UNaV (R = 0.89, P < 0.0001), UKV (R = 0.82, P < 0.0001) and UureaV (R = 0.89, P < 0.0001) significantly, the night/day ratio of V was correlated with the night/day ratios of UNaV (R = 0.81, P < 0.0001), UKV (R = 0.53, P = 0.004) and UureaV (R = 0.63, P = 0.0005). However, multiple regression analysis (Table 3) showed that the night/day ratio of V was independently determined only by natriuresis, night/day ratio of UNaV (P = 0.001), but not by the night/day ratios of UKV (P = 0.7), UureaV (P = 0.2), CH2O (P = 0.3) or MAP (P = 0.1).
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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The present study demonstrated that as renal function deteriorated, nocturnal diuresis was enhanced without affecting whole-day urinary volume in patients with CKD. This observation is consistent with classical recognition that a precocious and ubiquitous symptom of CKD is nocturia [2,3]. We assume that ‘nocturnal’ polyuria may be related to osmotic diuresis due to natriuresis rather than due to water diuresis.
We have recently reported that urinary sodium excretion during the night is enhanced as renal function deteriorates [4] and as the circadian rhythm of BP becomes non-dipper type [4–6], suggesting that nocturnal polyuria may be based on pressure-natriuresis during the night. On the other hand, it has been empirically thought that the capability to concentrate urine is impaired as renal function deteriorates [1,2], causing nocturnal polyuria as a precocious symptom of CKD. In fact, CH2O was shifted significantly from negative to positive values as renal function deteriorated in this study. When urinary osmolality becomes relatively isotonic due to a concentrating defect as the renal function deteriorates, urinary volume is obligated by osmotic diuresis rather than CH2O. Our results that the night/day ratio of urine volume was correlated with the night/day ratios of UosmV and therefore Cosm, but not with the night/day ratio or the day–night difference in CH2O are consistent with the idea. Nocturnal reduction in UosmV was significantly diminished, and the night/day ratio of UosmV was finally inverted from 0.8 ± 0.1 in group A to 1.4 ± 0.1 in group C as renal function deteriorated, while the day–night difference in CH2O was not affected by the degree of renal dysfunction, also being consistent with this idea. Therefore, it is clear now that osmotic diuresis rather than free-water diuresis creates nocturnal polyuria accompanied by renal dysfunction in CKD.
Although daily urinary volume is reported to be determined mainly by urea and total osmolar excretions [1], it remains unknown why urinary volume and osmotic diuresis is enhanced during the night in chronic renal failure [9–11]. Our present study, especially based on multiple regression analysis, suggested that osmotic diuresis due to natriuresis, rather than urea or potassium excretion was the main determinant to explain enhanced urinary volume during the night. We previously reported that, in patients with essential hypertension as BP became more sodium sensitive, nocturnal decline in BP was diminished [12], and that renal function is one of the major factors determining sodium sensitivity [13,14]. Therefore, our previous [4] and present findings that as renal function deteriorates, the nocturnal decline in BP is less pronounced, seems reasonable. These ideas are compatible with high sodium sensitivity of BP in CKD, reported even when a relatively normal renal function is maintained [15,16] and becomes much higher as renal function deteriorates [17]. As we previously proposed for non-dipping mechanisms in sodium-sensitive hypertension [5,6,12,18], our findings may further implicate that the diminished sodium excretory capability in CKD determines the circadian rhythm of BP. Defect in sodium excretory capability, which becomes more evident as the renal function deteriorates, causes MAP during the night to be elevated (that is nocturnal hypertension or non-dipper) to compensate for diminished natriuresis during the day and to enhance pressure natriuresis during the night. Please note our results that nocturnal natriuresis was enhanced without affecting its whole-day excretion rate, indicating that natriuresis during the day was impaired. Similarly, we recently showed in healthy kidney donors that the nocturnal dip in BP is diminished after unilateral nephrectomy without significantly affecting the absolute levels of BP [19]. In fact, there was a significantly positive relationship between the night/day ratio of MAP and the night/day ratio of natriuresis in the present study, as we previously showed [4,5]. There was also a significant positive relationship between the night/day ratios of both MAP and V. The night/day ratio of MAP was not correlated with night/day ratios of UureaV or UKV. Our proposal is consistent with the recent report by Bankir and colleagues [20] that some subjects exhibited a reduction in sodium excretion during the day and a compensatory rise during the night, and that this low diurnal natriuresis was associated with diminished nocturnal BP fall. Finally, we assume that nocturnal natriuresis based on pressure-natriuresis during the night resulted in nocturnal polyuria.
There are several limitations in this study. First, our subjects were limited to particular patients whose BP remained almost normal on a relatively low sodium diet alone without antihypertensive agents or diuretics. Second, the present study is cross-sectional, but not longitudinal. Since we measured data only at the single point, potential day-to-day variability could not be considered. Third, proteinuria and resultant hypoalbuminaemia may cause a shift of fluid into the interstitial space, although massive oedematous state was not included in this study. Such fluid shift possibly contributed to the disturbance in the circadian rhythm of urinary volume. Finally, we enrolled a small number of patients (n = 9) with CKD of different K/DOQI stages. It should therefore be noted that our study could not establish a clear cause–effect relationship at all.
In conclusion, the present study demonstrated that in CKD patients with reduced renal function, circadian rhythms of diuresis and natriuresis were also disturbed in addition to the BP rhythm. The degree of these disarrangements was enhanced as renal function deteriorated. Nocturnal polyuria accompanied by CKD seems to originate in osmotic diuresis, by enhanced nocturnal pressure-natriuresis, rather than free-water diuresis, by a diminished concentrating ability of urine. Precise mechanisms on how such pressure-natriuresis is enhanced during the night remain unsolved. Further studies are clearly required to establish the findings and the cause–effect relationship.
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Acknowledgments |
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This work is supported by Research Grants for Cardiovascular Diseases (C-2001–5) from the Ministry of Health and Welfare of Japan, as well as Grants from Nagoya City University, Salt Science Research Foundation (No. 04C1), Metabolic Disorders Treatment Research Foundation, Aichi Kidney Foundation and Japan Cardiovascular Research Foundation, and Grant-in-Aid for Scientific Research (C) from Ministry of Education, Culture, Sports, Science and Technology of Japan through Japan Society for the Promotion of Science.
Conflict of interest statement. None declared.
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Accepted in revised form: 14. 3.06
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