Diurnal Anti-Diuretic-Hormone Levels in Enuretics

0022-5347/85/1345-1029$02.00/0 Vol. 134, November

THE JOURNAL OF UROLOGY

Copyright © 1985 by The Williams & Wilkins Co.

Printed in U.S.A.

DIURNAL ANTI-DIURETIC-HORMONE LEVELS IN ENURETICS J. P. N0RGAARD, E. B. PEDERSEN

AND

J. C. DJURHUUS*

From the Institute of Experimental Clinical Research, University of Aarhus and Department of Medicine C, Aarhus Kommunehospital, Aarhus, Denmark

ABSTRACT

The diurnal antidiuretic hormone levels were studied in eleven enuretics and related to urine production and functional bladder capacity. A fluid deprivation test monitoring antidiuretic hormone levels was undertaken in four patients. The study suggests that the normal increase in nighttime antidiuretic hormone levels is absent in enuretics, who show a stable hormone level both day and night. Consequently the volume of night urine production approximates day urine production per hour. The functional bladder capacity was clearly exceeded at night in eight of eleven patients. The fluid deprivation test showed a normal response to fluid deprivation. In conclusion, the study adds further evidence that bladder capacity is a major factor in enuresis. Urine volumes that exceed bladder capacity at night may be caused by a lack of diurnal rhythmicity in antidiuretic hormone levels. The treatment of bed-wetting is "multi-modal," ranging from pharmaceutical to electrophysiological approaches. Pharmacotherapy is directed towards reducing the contractility of the bladder or the depth of sleep. 1• 2 The electrophysiologic technique using a bell and pad system is widely employed, waking the enuretics during the act of micturition and aiming to develop a reflex arousal resulting in nightly continence. The reported success rates using both types of treatments vary. The preferred treatment is either a tricyclic antidepressant or the bell and pad system 1 but no treatment has a predictable effect and relapses are frequent. A new principle in the treatment of enuresis was recently introduced using synthetic antidiuretics (DDAVP (1-desamino-8-D-arginine-vasopressin) ). 3- 5 The theoretical benefit may be that DDAVP might diminish the overnight production of urine and thereby prevent enuresis, since one theory of the pathogenesis of enuresis assumes that wetting only occurs when the normal functional bladder capacity is exceeded. 6 This theory is supported by the results of our sleep investigations in enuretics. 7 •8 We showed during sleep cystometry that enuresis occurs at the individual awake maximum bladder capacity, and was independent of depth of sleep. If the bladder capacity has to be exceeded before enuresis occurs, enuretics with normal bladder capacity might have abnormally low night plasma levels of arginine vasopressin (AVP). It has been shown that in normal non-enuretic adults AVP secretion is increased during the night, reaching significantly higher levels than in the day. 9 The secretion of arginine vasopressin (A VP) regulates the urine output. In normal non-enuretic adults the night plasma level of AVP is significantly higher than the day-time level, preventing a large urine output at night. A factor in the pathogenesis of enuretics may therefore be an abnormality in the rhythmicity of AVP production. In order to test this hypothesis we investigated patients with severe nocturnal enuresis, measuring the ratio between urine production during the night and in the daytime, the diurnal variation in AVP, urinary concentrating ability and bladder capacity, and studying the relationship between these parameters. MATERIALS AND METHODS

Eleven patients were investigated, five men (mean age 19 years, range 7-38 years) and six women (mean age 22 years, Accepted for publication June 21, 1985. * Requests for reprints: Institute of Experimental Clinical Research, University of Aarhus, DK-8000 Aarhus C, Denmark.

range 17-35 years) all with severe nocturnal enuresis refractory to conventional therapy. AVP and serum osmolality (SosM) were determined every third hour throughout a 24-hour period. Simultaneously a fractional three hour urine collection was performed from voided urine in the daytime and during sleep by means of a transurethral catheter. A maximum fluid intake of 30 cc/kg./24 hours was imposed. Smoking was not allowed during the investigation. Blood samples for AVP measurements were taken after the patients had been in the supine position for at least 30 minutes. All the patients underwent a urodynamic investigation. 10 The cystometries were performed using transurethral techniques in 10 patients and suprapubic in one. A fluid deprivation test was performed in four patients. After a normal breakfast, a 24-hour period of fluid deprivation was begun with measurements of AVP, SosM, urine osmolality (UosM) and fractional urine output. AVP was measured by radioimmunoassay as previously described, a modification of the method published by Robertson et al. 11 Radioimmunoassay was performed after precipitation of plasma proteins with cold acetone after extraction of lipids with petroleum ether. Osmolal concentrations in serum and urine were determined with a 65-31 Advanced Osmometer. RESULTS

Urine production. The distribution of the urine production in the awake state and during sleep is shown in table 1. Nine patients (no. 1, 2, 3, 4, 6, 8, 9, 10, 11) had an overnight urine production clearly exceeding their bladder capacity when awake, while two (no. 5, 7) had nocturnal urine production which approximately corresponded to their bladder capacity. Four patients (no. 2, 4, 5, 10) had a pronounced decrease in urine production during sleep, expressed as a ratio between the awake and sleeping urine production from 1.28 to 2.27. Six patients (no. 1, 3, 6, 7, 8, 11) showed an increase in urine output during sleep with a ratio from 0.84 to 0.39. In one patient (no. 9) the ratio was close to 1. In four patients (no. 1, 2, 3, 8) a relatively large urine production was observed during the first hours after the onset of sleep (fig. 1), whereas urine production was more equally distributed throughout the night in the other seven. Patient no. 11 was found to have central diabetes insipidus. Arginine-uasopressin and serum osmolality. Fig. 2A depicts the variation in AVP. The mean levels throughout 24 hours varied from 2.57 pmol./1. to 3. 72 pmol./1., but without an

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N0RGAARD, PEDERSEN AND DJURHUUS

TABLE

1. Distribution of urine production throughout the 24 hour period, with calculation of diuresis during sleep in relation to awake urine

production Pt. No.

Age/Sex

Urine Production Day/Night

1 2 3 4 5 6 7 8 9 10 11

39 m 35 f 16 m 16 f 14m 24 f 17 f 15 f 7m 18 m 30 f

1110/1095 3200/800 800/810 1250/370 1600/350 525/550 925/495 1050/675 280/240 750/290 3100/2025

Sleep Duration

Ratio Awake/ Sleep Urine Production

Estimated Frequency of Enuresis Per Night

Bladder Capacity

Sleep Production as % of Mean Capacity

8 h 7,25 h 9 h 7 h 8 h 7 h 6 h h 8 11,5 h 8 h 8,5 h

0,51 1,72 0,59 1,39 2,27 0,39 0,62 0,78 1,08 1,28 0,84

2 2 2-3 1 1 1 1 1-2 ? 1 2-3

494,569 387,389 298,260 165,106 315,355 400,294 480,490 421,513 75,47 201,295 677,667

205 206 290 226 104 158 102 145 393 117 301

Urine production in relation to functional bladder capacity is also shown. Mean bladder capacity is estimated from maximal capacities of two cystometries. 600 500 400 300 200 100

A. V. 15 YEARS d' bladder cap.

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8pm-12pm

Oam-4am

4am-8am

TIME

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FIG. 1. Example of urine output distribution throughout 24 hour period with normal fluid intake in two patients. Arrow indicates onset of sleep.

FIG. 2A. AVP levels throughout first 24 hours with normal fluid intake. Total range is shown, hatched areas with median value and first quartile on each side. 15

apparent or statistically significant difference. However, there was a tendency toward lower levels in the period from 8 p.m. to 12 p.m. and higher in the period from 4 a.m. to 8 a.m. SosM was constant in all the patients. In figure 3 a single patient investigation is shown as an example. Fluid deprivation. A urinary concentrating test was performed in 4 patients (table 2). Urine volume was clearly reduced and UosM increased to approximately 800 to 1000 mosmol./kg. AVP increased significantly during water deprivation from 3.15 pmol./1. (range 1.67 to 4.80) to 8.79 pmol./1. (range 3.91 to 13.17) (p < 0.01) as shown in fig. 2B. Bladder capacity. Hyperreflexia was present during bladder filling in two patients (no. 3 and 9), while the rest had normal cystometries. The bladder capacity was in the normal range in all patients except in no. 9, who had a small hyperreflexic bladder with a mean capacity of 65 cc and in no. 4 who had a small but stable bladder.

FLUID DEPRIVATION

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FIG. 2B. Same as 2A during fluid deprivation.

DISCUSSION

DDAVP (1-desamino-8-D-arginine-vasopressin) has recently been used in the treatment of nocturnal enuresis with the aim of lowering urine production during sleep. It has already been established that some enuretics have a relatively large overnight production of urine, 18 a finding contradicted by other studies 14 • 15 where a 2 to 1 ratio in daytime/nighttime volume was shown both in enuretic and nonenuretic children. None of these studies, however, considered the importance of functional bladder capacity. In this study we found that the urine production in all eleven patients exceeded their functional bladder capacity to a maximum of 393 per cent, a condition favoring one or more enuretic episodes. 7 •8

Thus, two factors may explain enuresis, either polyuria or a low bladder capacity. Supporting the first factor, the bladder capacities were normal in all but two of the patients. Moreover six patients increased urine diuresis during sleep, favoring nocturnal polyuria as the causative factor. In a previous study 9 a diurnal variation of AVP was found in normal men. Plasma AVP concentration was significantly higher at night and it was suggested that the normal observed nocturnal decrease in urine output14 was at least to some extent explained by this rise in AVP. In the present study no diurnal variation was found in AVP in enuretics, suggesting that a relative lack of AVP at night could be responsible for a high urine output.

DIURNAL ANTI-DIURETIC-HORMONE LEVELS IN ENURETICS 10

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investigation of the diurnal diuresis is proposed as part of the routine investigation of enuretics before selecting any therapy. The findings described above seem to explain why enuretics void during sleep, but no explanation could be derived from the AVP measurements concerning the wide variation in day/night urine production ratio. That question together with continued studies of a possible defect in the arousal mechanism are matters for future research. REFERENCES

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FIG. 3. Example of AVP levels and SosM in single patient. Upper tracing showing normal 24 hour period, lower tracing 24 hour period of fluid deprivation with significant increase in AVP concentration. TABLE 2.

Urine osmo/,ality and urine output during fluid deprivation in four patients

8 a.m.-2 p.m. 2 p.m.-8 p.m. 8 p.m.-24 p.m. 0 a.m.-4 a.m. 4 a.m.-8 a.m.

Diuresis

UosM

Pt. No. 1

2

3

8

1

2

3

8

756 816 654 946 988

519 612 692 775 629

801 842 1213 1054 1151

245 640 830 1187 1252

180 275 75 100 75

375 175 220 180 80

250 260 45 55 75

150 75 125 50 60

The main stimulatory factor for AVP secretion is increased SosM and a reduced plasma volume. 16 We showed a normal concentrating ability in enuretics, in agreement with another study. 17 Thus the response to fluid deprivation and increments in SosM was normal.1 8 In a study by Deane et al. 17 which compared the AVP concentration in adult enuretics with a concentration in age-matched controls, the only difference was a significantly higher concentration of AVP after fluid deprivation in enuretics. The fluid deprivation was, however, brief and urine production was not measured. Therefore the fluid intake prior to deprivation might invalidate the conclusions concerning urine production during sleep. In the supine position central blood volume is increased and AVP secretion reduced via volume receptors. Since AVP secretion is lower in enuretics, it is possible that volume receptors have an abnormal sensitivity, which may then cause the apparently reduced AVP level. It therefore seems reasonable to treat at least some enuretics with DDAVP or other drugs decreasing nocturnal urine output to a volume less than the functional bladder capacity. Hence

1. Mikkelsen, E. J. and Rappoport, J.: Enuresis: psychopathology, sleep-stage and drug response. Urol. Clin. N. Am., 5: 2, 1980. 2. Thorup, J. and Hansen, B.: The effect of emepromium bromide on urodynamic findings and clinical symptomes in enuretic children. Proceedings ICS 12th Annual Meeting, Leiden 1982. 3. Dimson, S. B.: Desmopressin as a treatment for enuresis. Lancet, I: 1977, 1960. 4. Sandeman, Kj0ller: Enuresis nocturna behandlet med minurin (DDAVP). Ugeskr. Laeger, 43: 3281, 1984. 5. Tuvemo, T.: DDAVP in childhood nocturnal enuresis. Acta Paed. Scand., 67: 753, 1978. 6. Troup, C. V. and Hodgson, D. N.: Nocturnal functional bladder capacity in enuretic children. J. Urol., 105: 129, 1971. 7. N0rgaard, J. P., Hansen, J. H., Petersen, B. D., Knudsen, N., Nielsen, J. B. and Djurhuus, J. C.: Overnight monitoring in children with nocturnal enuresis. Urology (In press.) 8. N0rgaard, J. P., Petersen, B. S., Hansen, J. H., Nielsen, J. B. and Djurhuus, J.C.: Cystometries performed at sleep in children with nocturnal enuresis. Proceedings ICS 14th Annual Meeting, Innsbruck, 1984. 9. George, P. L. C., Messerli, F. H., Genest, J., Nowaczynski, W., Boucher, R., Kuchel, 0. and Roja-Ortega, M.: Diurnal variation of plasma vasopressin in man. J. Clin. Endocrinol. Metabol., 41: 332, 1975. 10. N0rgaard, J. P., S0rensen, S. S. and Djurhuus, J. C.: Functional bladder neck obstruction in women. Urol. Int., 39: 207, 1984. 11. Pedersen, E. B., Danielsen, H. and Spencer, E. S.: Effect of indapamid on renal plasma flow, glomerular filtration rate and arginin vasopressin in plasma in essential hypotension. Eur. J. Clin. Pharmacol., 26: 543, 1984. 12. Robertson, G. L., Mahr, E. A., Athat, S. and Sinha, T.: Development and clinical application of a new method for the radioimmuno-assay of arginine vasopressin in human plasma. J. Clin. Invest., 52: 2340, 1973. 13. Poulton, E. M. and Hinden, E.: Classification of enuresis. Arch. Dis. Child., 28: 392, 1953. 14. Mills, J. N.: Diurnal rhythm in urine flow. J. Physiol., 113: 528, 1951. 15. Vulliamy, D.: The day and night output of urine in enuresis. Arch. Dis. Child., 31: 439, 1959. 16. Robertson, G. L.: The regulation of vasopressin function in health and disease. Recent Prog. Horm. Res., 33: 333, 1977. 17. Deane, A. M., Capper, V., Forsling, M. L., Hindmarsh, J. R. and Wickham, J. E. A.: ADH-levels and concentrations abilities in adult enuresis. Proceedings 6th EAU-meeting, Copenhagen, 1984. 18. Pedersen, E. B., Danielsen, H., Nielsen, A. H., Knudsen, F., Jensen, T., Kornerup, H. J. and Madsen, M.: Relationship between urinary concentrating ability, arginine vasopressin in plasma and blood pressure after renal transplantation. Scand. J. Clin. Lab. Invest. (In press.)