Effect of Indomethacin on Desmopressin Resistant Nocturnal Polyuria and Nocturnal Enuresis

Effect of Indomethacin on Desmopressin Resistant Nocturnal Polyuria and Nocturnal Enuresis Konstantinos Kamperis,* Søren Rittig, Wendy F. Bower and Jens C. Djurhuus From the Department of Pediatrics, Aarhus University Hospital, Skejby and Institute of Clinical Medicine, Aarhus University (JCD), Aarhus, Denmark

Purpose: We evaluated the acute effect of indomethacin on renal water and solute handling in children with coexisting monosymptomatic nocturnal enuresis and desmopressin resistant nocturnal polyuria, and in healthy controls. Materials and Methods: A total of 23 subjects were recruited, consisting of 12 children with monosymptomatic nocturnal enuresis and nocturnal polyuria with partial or no response to desmopressin, and 11 age matched controls. Children completed a 48-hour inpatient study protocol consisting of fractional urine collections and blood samples. Sodium and water intake were standardized. During the second night a dose of 50 mg indomethacin was administered orally before bedtime. Diuresis, urine osmolalities, clearances and fractional excretions were calculated for sodium, potassium, urea, osmoles and solute-free water. Renin, angiotensin II, aldosterone and atrial natriuretic peptide were measured in plasma. Prostaglandin E2 was measured in urine. Results: Indomethacin markedly decreased the nocturnal sodium, urea and osmotic excretion in children with enuresis and controls. The overall effect on nocturnal urine output was inconsistent in the group with enuresis. Subjects in whom nocturnal diuresis was decreased following administration of indomethacin remained dry. Conclusions: Prostaglandin inhibition leads to antidiuresis, reducing the amount of sodium, urea and osmotic excretion in children with monosymptomatic nocturnal enuresis and desmopressin resistant nocturnal polyuria. The sodium regulating hormones do not seem to mediate these processes. The overall effect in desmopressin nonresponders with nocturnal polyuria is variable. The extent to which indomethacin can be applied in the treatment of enuresis needs further evaluation.

Abbreviations and Acronyms ALDO ⫽ aldosterone ANP ⫽ atrial natriuretic peptide dDAVP ⫽ desmopressin MNE ⫽ monosymptomatic nocturnal enuresis MVV ⫽ maximum voided volume PGE2 ⫽ prostaglandin E2 TcH2O ⫽ solute-free water reabsorption Submitted for publication March 5, 2012. Study received local ethics committee approval. Supported by grants from the University of Aarhus Research Foundation, Egmont Foundation and KE Jensen Foundation. * Correspondence: Department of Pediatrics, Aarhus University Hospital, Skejby, Brendstrupgaardsvej 100, 8200 Aarhus N, Denmark (e-mail: [email protected]).

Key Words: diuretics, osmotic; natriuresis; polyuria; prostaglandins NOCTURNAL enuresis is a common and distressful condition in childhood with a multifactorial background. Production of abnormally large quantities of urine at night and impairment of bladder reservoir function are causal factors of an enuresis episode. The blunted diurnal rhythm of arginine vasopressin secretion observed in patients with enuresis seems responsible for the observed nocturnal polyuria in

some.1,2 Treatment with desmopressin can restore the normal nyctohemeral variations in urine production, ensuring dry nights.3 However, not all children with enuresis and nocturnal polyuria demonstrate an adequate response to desmopressin. Impairment of normal bladder reservoir function can in some cases explain the nonoptimal response,4 although there are cases where the antidiuretic effect of desmo-

0022-5347/12/1885-1915/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION

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pressin seems absent. Alternative mechanisms hypothesized to cause desmopressin resistant nocturnal polyuria include excess urinary excretion of sodium and potassium, hypercalciuria, abnormal urea and prostaglandin excretion, changes in diurnal rhythms of angiotensin and aldosterone production, and abnormal diurnal glomerular filtration rates.5–10 Cyclooxygenase inhibitors share antidiuretic properties and are used in clinical settings of excess polyuria, nephrogenic diabetes insipidus and other tubulopathies.11 During the last few years these agents have been tested in patients with enuresis, with promising results.12–15 Since evidence suggests that certain populations of children with enuresis produce excessive amounts of prostaglandins during the night,8,16 cyclooxygenase inhibition may represent a therapeutic alternative in those not responding to conventional therapeutic interventions. We evaluated the acute effects of indomethacin on renal water and solute handling in a highly selected population of children with desmopressin resistant monosymptomatic nocturnal enuresis and nocturnal polyuria, and in healthy controls.

MATERIALS AND METHODS The study protocol was approved by the local ethics committee, and informed consent was acquired from all participants. The protocol conformed to the recommendations for good clinical practice (CPMP/ICH/135/95) and was registered with clinicaltrials.gov (NCT00226122).

Study Subjects A total of 12 children 7 to 14 years old with MNE and nocturnal polyuria and 11 matched controls were included in the study. All subjects were recruited from the outpatient clinics of the Center for Child Incontinence, Skejby. Inclusion criteria for patients with enuresis were monosymptomatic enuresis, MVVs greater than 65% of age expected volume, normal uroflowmetry and residual urine, and unremarkable clinical examination. Subjects exhibited no dDAVP response, defined as less than 50% reduction in the number of wet nights on 2-week frequency volume charts with incremental doses of either dDAVP spray (20 to 40 ␮g) or tablets (0.2 to 0.4 mg). Average nocturnal urine volumes on wet nights exceeding 130% of the expected MVV for age qualified for nocturnal polyuria.

Study Design Participants were admitted to the department of pediatrics for 48 hours following an adaptation night. Blood samples were taken every 4 hours through a heparinized cannula during the entire experimental protocol. Subjects remained seated for 10 minutes before blood sampling. Blood samples were immediately centrifuged at 4C and stored at ⫺20C unless immediately analyzed. Urine was fractionally collected at 4-hour intervals following spontaneous voiding. A Conveen® Security⫹ Uridome (boys) or an adhesive stoma (Assura®) facilitated urine collections

from enuresis episodes. A diaper was used to measure urine loss in case of collecting system failure in 2 girls. Before the second night of the experimental period and at bedtime 50 mg indomethacin was administered orally. Fluid and total sodium intake were standardized to 30 ml/kg and 3 mmol/kg, respectively, and supervised and recorded by a clinical dietitian. Meals were served at 8:15 a.m., 12:00 p.m. and 5:30 p.m.

Biochemistry Determinations Determination of plasma sodium, potassium, creatinine and urea measurements was carried out at the department of clinical biochemistry (Ektachem 700XRC, Kodak, Rochester, New York). In urine the sodium and potassium concentrations were measured using flame photometry (FCM6341 and MFM6350, Eppendorf AG, Hamburg, Germany). Plasma and urine osmolalities were measured by the freezing point depression method (Advanced® model 3900 osmometer). Plasma ANP was measured as described previously.17 The limit of detection was 1.5 pg/ml, whereas the intraassay and interassay coefficients of variation were 10% and 12%, respectively. Plasma angiotensin II was determined by radioimmunoassay as described previously,18 with modifications using a rabbit anti-angiotensin II antibody (Ab-5-030682, P. Christensen, Glostrup Hospital, Glostrup, Denmark). Intra-assay and interassay coefficients of variation were 9% and 13%, respectively, and the limit of detection was 1.4 pg/ml. Radioimmunoassay (Active® aldosterone coated tube radioimmunoassay kit) was used to determine plasma aldosterone. The assay was performed with an intra-assay coefficient of variation of 7%, an interassay coefficient of variation of 13% and a minimum detection limit of 25 pg/ml. Plasma activated renin was directly measured (Quest Diagnostics, Nichols Institute, San Juan Capistrano, California). Intra-assay and interassay coefficients of variation were 2% and 8%, respectively, and detection limit was 1.4 ␮U/ml. Urine PGE2 was measured via an enzyme immunoassay for metabolites (Cayman Chemical Company, Inc., Ann Arbor, Michigan), which allowed us to reliably estimate the urinary PGE2 levels in urine at collection. Interassay and intra-assay coefficients of variation were ap-

Table 1. Patient characteristics and demographics

Mean ⫾ SE age (yrs) No. gender: M F Mean ⫾ SE body wt (kg) Mean ⫾ SE height (cm) Mean ⫾ SE MVV (ml) Mean ⫾ SE MVV-to-expected MVV for age Mean ⫾ SE urine output on nights with enuresis (ml)

Pts

Controls

10.0 ⫾ 0.4

11.5 ⫾ 0.6

8 2 36 ⫾ 2 143 ⫾ 3 263 ⫾ 39 0.80 ⫾ 0.06

6 5 43 ⫾ 3 150 ⫾ 4 Not applicable Not applicable

377

⫾ 15

Not applicable

INDOMETHACIN IN PATIENTS WITH NOCTURNAL ENURESIS AND POLYURIA

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Table 2. Baseline and post-indomethacin treatment values Pts

Urine flow (ml/kg/hr) Urinary osmolality (mosm/kg) Sodium excretion (mmol/kg/hr) Sodium clearance (ml/min) % Fractional sodium excretion Potassium excretion (mmol/kg/hr) Potassium clearance (ml/min) % Fractional potassium excretion Urea excretion (mmol/kg/hr) Urea clearance (ml/min) % Fractional urea excretion Osmolar excretion (mosm/kg/hr) Osmolar clearance (ml/min) Solute-free water reabsorption (ml/min) Glomerular filtration rate (ml/min) Prostaglandin E2 excretion (ng/kg/hr)

Controls

Mean ⫾ SE Baseline

Mean ⫾ SE Posttreatment

Mean ⫾ SE Baseline

Mean ⫾ SE Posttreatment

1.27 ⫾ 0.16 561 ⫾ 28 0.10 ⫾ 0.01 0.45 ⫾ 0.05 0.50 ⫾ 0.05 0.035 ⫾ 0.004 5.18 ⫾ 0.41 5.76 ⫾ 0.43 0.33 ⫾ 0.02 47.31 ⫾ 2.77 52.09 ⫾ 1.82 0.68 ⫾ 0.06 1.46 ⫾ 0.10 0.71 ⫾ 0.05 95.6 ⫾ 8.1 0.22 ⫾ 0.03

0.90 ⫾ 0.17 605 ⫾ 86 0.03 ⫾ 0.01† 0.14 ⫾ 0.02† 0.17 ⫾ 0.03† 0.029 ⫾ 0.005 4.17 ⫾ 0.60 5.03 ⫾ 0.75 0.26 ⫾ 0.03* 32.57 ⫾ 2.33† 39.14 ⫾ 2.46† 0.44 ⫾ 0.05† 0.92 ⫾ 0.08† 0.42 ⫾ 0.08† 83.9 ⫾ 4.5 0.10 ⫾ 0.03*

0.74 ⫾ 0.08 684 ⫾ 85 0.06 ⫾ 0.01 0.34 ⫾ 0.05 0.34 ⫾ 0.04 0.024 ⫾ 0.002 4.25 ⫾ 0.36 4.56 ⫾ 0.46 0.22 ⫾ 0.01 45.69 ⫾ 3.58 46.80 ⫾ 1.36 0.45 ⫾ 0.03 1.17 ⫾ 0.10 0.61 ⫾ 0.08 99.9 ⫾ 9.2 0.13 ⫾ 0.01

0.52 ⫾ 0.08* 868 ⫾ 79* 0.04 ⫾ 0.01* 0.22 ⫾ 0.05* 0.23 ⫾ 0.05* 0.024 ⫾ 0.004 4.69 ⫾ 1.07 4.75 ⫾ 0.78 0.20 ⫾ 0.01 36.67 ⫾ 3.52† 38.36 ⫾ 1.59† 0.39 ⫾ 0.03 1.03 ⫾ 0.13 0.61 ⫾ 0.12 91.6 ⫾ 6.5 0.06 ⫾ 0.01†

* p ⬍0.05. † p ⬍0.001.

proximately 15% and 10%, respectively, and the detection limit was 2 pg/ml.

Statistical Analysis Excretions and clearances for the 5 clearance periods (8:00 a.m. to 12:00 p.m., 12:00 to 4:00 p.m., 4:00 to 8:00 p.m., 8:00 p.m. to bedtime and overnight) were calculated for electrolytes, creatinine, urea and osmoles using standard formulas. Solute-free water reabsorption was calculated using the formula, TcH2O ⫽ Cosm ⫺ Uflow, where TcH2O is solute-free water reabsorption, Cosm is osmolar clearance and Uflow is urine flow. Fractional excretions were

calculated using the formula, FEi (%) ⫽ [Ci/GFR] ⫻ 100, where FEi is fractional excretion of indomethacin, Ci is indomethacin clearance and GFR is glomerular filtration rate. Creatinine clearance was used for glomerular filtration rate estimations. Results are presented as mean ⫾ SE. To assess variations through time as well as to investigate for possible group-main effect interactions, data were subjected to analysis by repeat measurement ANOVA. T statistics were used for further comparisons between and within groups. The Pearson test was used for correlation analy-

Controls

-1.00

-0.75

-0.50

-0.25

0.00

U-flow (ml/kg.h)

Enuretic children

0.25

0.50

-1.00

-0.75

-0.50

-0.25

0.00

0.25

0.50

U-flow (ml/kg.h)

Figure 1. Change scores in diuresis for controls and children with enuresis. Most children responded with reductions in nocturnal urine production.

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INDOMETHACIN IN PATIENTS WITH NOCTURNAL ENURESIS AND POLYURIA

sis. SPSS®, version 13.0 was used for all statistical inference. Statistical significance was defined by a p value of less than 0.05.

RESULTS Of the initial population 2 children with enuresis did not experience an episode during the baseline night and were excluded from further analysis. Table 1 outlines the demographics and home recording data of the remaining subjects. There were no differences between the study groups in terms of age, weight, height or gender composition. Table 2 summarizes the principal parameters evaluated. Circadian Urine Production and Steady State There were no significant differences in diuresis (urine flow), electrolyte or osmolar excretion between the 2 days of the experimental protocol (data not shown). Plasma sodium and plasma osmolality levels displayed no significant variation during the 2 days, indicating steady state achievement.

3.0

p<0.05

Nocturnal Urine Output and Osmolality Indomethacin reduced mean ⫾ SE nocturnal urine volume by approximately 30% in controls (from 0.74 ⫾ 0.08 to 0.52 ⫾ 0.08, p ⬍0.05) and patients with enuresis (from 1.27 ⫾ 0.16 to 0.90 ⫾ 0.17, p ⫽ 0.09, figs. 1 and 2). However, patients with enuresis still had higher nocturnal diuresis compared to controls (table 2). Three of the children with enuresis were dry following administration of indomethacin. In these children indomethacin exhibited a more pronounced effect on diuresis (mean ⫾ SE decrease from 1.44 ⫾ 0.46 to 0.42 ⫾ 0.54 ml/kg per hour) compared to nonresponders (from 1.19 ⫾ 0.14 to 1.10 ⫾ 0.54 ml/kg per hour). Mean ⫾ SE urine osmolality increased significantly in controls to levels exceeding 850 mosm/kg but the corresponding changes were minimal in subjects with polyuria (from 561 ⫾ 28 mosm/kg at baseline to 605 ⫾ 86 mosm/kg after indomethacin, fig. 2). The children reaching the highest urine osmolalities following indomethacin were those responding to the agent (from 529 to 851 mosm/kg), whereas in

NS

1500

p<0.05

NS

Controls

Enuretic

NS

p<0.05

Uosm (mosm/kg)

Uflow (ml/kg.min)

2.5 2.0 1.5 1.0 0.5

Controls

Enuretic

NS

p<0.01

750 500

0

1.25

E-osm (mosm/kg.h)

1.5

TcH2O (ml/min)

1000

250

0.0

2.0

1250

1.0

0.5

1.00 0.75 0.50 0.25

0.0

Controls

Enuretic

0.00

Controls

Enuretic

Figure 2. Box plots show nocturnal levels of diuresis (Uflow), urine osmolality (Uosm), TcH2O and osmolar excretion (E-osm) for controls and children with enuresis at baseline (white bars) and following administration of indomethacin (shaded bars).

INDOMETHACIN IN PATIENTS WITH NOCTURNAL ENURESIS AND POLYURIA

nonresponders urine osmolality was paradoxically reduced after indomethacin (from mean ⫾ SE 571 ⫾ 34 to 458 ⫾ 65 mosm/kg). Creatinine clearance was not significantly altered following administration of indomethacin, although a trend was seen toward lower values (table 2). Urinary Electrolyte and Urea Excretion Indomethacin had a dramatic effect on renal sodium handling, reducing the nocturnal amount of sodium excreted in urine in controls and patients with enuresis (table 2). The effect on sodium excretion was evident in children responding to indomethacin (mean ⫾ SE decrease from 0.12 ⫾ 0.02 to 0.021 ⫾ 0.02 mmol/kg per hour) and nonresponders (from 0.09 ⫾ 0.02 to 0.041 ⫾ 0.01 mmol/kg per hour). Sodium clearance and fractional sodium excretion were similarly reduced (table 2 and fig. 3). In both groups studied the renal handling of potassium remained unchanged after administration of indomethacin. The amount of urea excreted in urine remained unchanged in response to indomethacin in controls 0.25

p<0.05

but was decreased in the group with enuresis, who also had higher baseline values compared to controls (table 2 and fig. 3). The effect was more pronounced in the subjects with enuresis responding to indomethacin (mean ⫾ SE decrease from 0.32 ⫾ 0.04 to 0.21 ⫾ 0.05 mmol/kg per hour) compared to nonresponders (from 0.34 ⫾ 0.03 to 0.30 ⫾ 0.03 mmol/kg per hour). The decrease in nocturnal clearance and fractional excretion of urea was evident in controls and patients with polyuria. We found change scores in fractional excretion of sodium and urea to be significantly correlated with change scores in diuresis (fig. 4). Renal Water and Overall Solute Handling Mean ⫾ SE solute-free water reabsorption remained unchanged in response to indomethacin in controls but was decreased in subjects with polyuria (from 0.71 ⫾ 0.05 to 0.42 ⫾ 0.08 ml per minute, p ⬍0.01). The failure of indomethacin to control solute-free water clearance was most evident in the nonresponders to indomethacin (mean ⫾ SE TcH2O de1.2

p<0.01

FE-Na (%)

E-Na (mmol/kg.h)

p<0.05

p<0.001

Controls

Enuretic

1.0

0.20 0.15 0.10

0.8 0.6 0.4

0.05

0.2

0.00

0.0 Controls

0.6

NS

Enuretic 0.6

p<0.05

p<0.001

0.5

0.5

0.4

0.4 FE-Ur (%)

E-Ur (mmol/kg.h)

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0.3 0.2 0.1 0.0

p<0.001

0.3 0.2 0.1

Controls

Enuretic

0.0

Controls

Enuretic

Figure 3. Box plots reveal nocturnal levels of sodium excretion (E-Na) and urea excretion (E-Ur), and fractional excretion of sodium (FE-Na) and urea (FE-Ur) for controls and children with enuresis at baseline (white bars) and following administration of indomethacin (shaded bars).

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INDOMETHACIN IN PATIENTS WITH NOCTURNAL ENURESIS AND POLYURIA

2.0

2.0

r = 0.55 p<0.05

1.5

D-Uflow

D-Uflow

1.5

r = 0.52 p<0.05

1.0

1.0

0.5

0.5

0.0

0.0

-0.5

-0.5 -0.2

0.0

0.2

0.4

0.6

0.8

0

5

10

D-FENa

15

20

25

D-FEUr

2.0

2.0

1.5

1.5

1.0

1.0

D-Uflow

D-Uflow

r = 0.55 p<0.05

0.5

0.0

0.5

0.0

r = 0.55 p<0.05 -0.5 -800

-0.5 -600

-400

-200

0

200

400

-0.2 -0.1

0.0

D-Uosm

0.1

0.2

0.3

0.4

0.5

0.6

D-Eosm

Figure 4. Correlation between nocturnal diuresis (Uflow) and fractional excretion of sodium (FENa) and urea (FEUr), as well as between corresponding change scores (D) of these parameters. Uosm, urine osmolality. Eosm, osmolar excretion.

creased from 0.67 ⫾ 0.09 to 0.32 ⫾ 0.09 ml per minute). Overall osmolar excretion and clearance were reduced by indomethacin, with the effect being more pronounced in subjects with enuresis responding to indomethacin (mean ⫾ SE decrease from 0.71 ⫾ 0.13 to 0.36 ⫾ 0.07 mosm/kg per hour in responders and from 0.68 ⫾ 0.07 to 0.48 ⫾ 0.06 mosm/kg per hour in nonresponders). Correlation analysis between change scores in osmolar excretion and urine flow yielded significant results (r ⫽ 0.60, p ⬍0.01, fig. 4).

cin, an effect seen more consistently in controls (from mean ⫾ SE of 35.8 ⫾ 5.5 to 30.2 ⫾ 5.6 ␮U/ml, p ⬍0.01) than subjects with polyuria (from 59.5 ⫾ 11.2 to 45.9 ⫾ 6.2 ␮U/ml, p ⫽ 0.06, fig. 5). Although urinary excretion of PGE2 was reduced in controls and subjects with polyuria, there were more dramatic decreases in PGE2 excretion in responders (mean ⫾ SE reduction from 0.22 ⫾ 0.06 to 0.04 ⫾ 0.01) than in nonresponders (from 0.23 ⫾ 0.05 to 0.14 ⫾ 0.03).

Measurements in Plasma and Urine Excretion of PGE2 Administration of indomethacin did not alter the levels of electrolytes, urea or creatinine in plasma, nor did it affect plasma levels of ANP, angiotensin II or ALDO (fig. 5). There was a slight decrease in the nocturnal levels of renin in response to indometha-

This study targets a highly selected population of children with monosymptomatic enuresis, nocturnal polyuria and dDAVP resistance. These patients represent a small population that is treatment resistant.19 Mechanisms outside the vasopressin-aquaporin axis, including a role for prostaglandins, have been hypothesized to be responsible for the noctur-

DISCUSSION

INDOMETHACIN IN PATIENTS WITH NOCTURNAL ENURESIS AND POLYURIA

Enuresis 80

60

60

40

40

20

20

300

300

ALDO (pg/ml)

80

200

100

40

40

30 20

ANG II (pg/ml)

30 20

20

30 20 10

10 0

30

40

40 ANG II (pg/ml)

200

100

ANP (pg/ml)

ANP (pg/ml)

ALDO (pg/ml)

renin (mcU/ml)

Control

24:00

04:00

time (hs)

08:00

0

24:00

04:00

08:00

time (hs)

Figure 5. Nocturnal levels of renin, ALDO, ANP and angiotensin II (ANG II) during baseline (open circles) and following administration of indomethacin (shaded circles).

nal polyuria in this subgroup of children.8,9,20,21 Clinical studies of enuresis indicate that cyclooxygenase inhibition may lead to successful treatment.12,15,22 However, these studies are performed in often poorly characterized populations of children with enuresis. Our current knowledge regarding the precise renal properties of prostaglandin inhibition in children with enuresis remains limited. Indomethacin reduces nocturnal urine output in healthy children by approximately 30%. Considerable variability in the actions of indomethacin was noted, reflecting the range of the results provided by other clinical studies. Natochin and Kuznetsova reported a response to diclofenac as high as 33%,12 while Varan et al did not find indomethacin to be effective.14 Others have observed indomethacin to be superior to placebo in unselected populations.13,15 A recent study of a large population of children with enuresis revealed ibuprofen to be superior to placebo.23 The inconsistent effects of prostaglandin inhibition may also reflect the existence of sub-

1921

populations of children with enuresis with distinct pathophysiological characteristics. The population recruited in this study was homogeneous. These are the typical children considered for treatment with prostaglandin inhibitors, ie children with normal bladder reservoir function, nocturnal polyuria and desmopressin resistance. The antidiuretic effect seems attributable to the potent antinatriuretic properties of indomethacin,24,25 as well as to considerable reductions in urea and overall osmotic clearance. These factors have all been implicated in the pathophysiology of MNE. The antinatriuretic effect of indomethacin is probably the result of direct tubular sodium reabsorption enhancement without the participation of the regulating hormones of the renin-angiotensin-aldosterone system. The potent antinatriuretic effect of indomethacin is present even in children where the agent fails to adequately control nocturnal urine output. However, in these children renal water handling seems altered following indomethacin administration, with significantly lower TcH2O values seen during treatment nights. This result led to lower nocturnal urine osmolalities in the group with enuresis. This finding is rather unexpected, taking into account the previously described positive effect of prostaglandin inhibition on renal water reabsorption.26,27 This excess excretion of solute-free water may be the reason for the inadequate indomethacin response in our study population. Since marked differences between indomethacin responders and nonresponders appear in terms of the degree of urinary PGE2 inhibition, it could be hypothesized that the differences in diuresis may be a consequence of variable indomethacin bioavailability and pharmacodynamics. Indeed, several factors may influence indomethacin pharmacokinetics,28 and dose response studies of prostaglandin inhibitors in children with enuresis do not exist. Indomethacin has a half-life of 4.5 hours, and it may be that in some subjects the dose of indomethacin needed to achieve maximal antidiuresis overnight is considerably higher. Indomethacin exerts significant effects on urea excretion in subjects with enuresis and controls. The mechanisms responsible are not well understood, but the antagonistic effect of PGE2 on arginine vasopressin may be implicated.29 Urea is an important molecule for the buildup of the interstitial osmolality gradient necessary for water reabsorption. Urea transporters are upregulated by arginine vasopressin, whereas PGE2 acts as an antagonist in these pathways.30 The clinical significance of indomethacin modulation of renal urea handling is unclear but evidence suggests that certain populations of patients with enuresis may have excess nocturnal urea excretions.8 Normalization of renal urea handling may contribute to the clinical effects of the agent in enuresis.

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INDOMETHACIN IN PATIENTS WITH NOCTURNAL ENURESIS AND POLYURIA

CONCLUSIONS Indomethacin has a marked effect on nocturnal sodium, urea and overall osmotic excretion in healthy children and in those with enuresis and nocturnal polyuria. The effect on nocturnal urine output seems variable in subjects with enuresis but rather consistent in healthy controls. The degree of PGE2 inhibition seems related to the degree of antidiuresis. In

children where desmopressin fails to control nocturnal urine output indomethacin represents a possible treatment modality.

ACKNOWLEDGMENTS Jane Knudsen provided technical assistance.

REFERENCES 1. Rittig S, Knudsen UB, Norgaard JP et al: Abnormal diurnal rhythm of plasma vasopressin and urinary output in patients with enuresis. Am J Physiol 1989; 256: F664. 2. Aikawa T, Kasahara T and Uchiyama M: Circadian variation of plasma arginine vasopressin concentration, or arginine vasopressin in enuresis. Scand J Urol Nephrol Suppl 1999; 202: 47. 3. Glazener CM and Evans JH: Drugs for nocturnal enuresis in children (other than desmopressin and tricyclics). Cochrane Database Syst Rev 2000; 3: CD002238. 4. Yeung CK, Chiu HN and Sit FK: Bladder dysfunction in children with refractory monosymptomatic primary nocturnal enuresis. J Urol 1999; 162: 1049. 5. Rittig S, Knudsen UB, Norgaard JP et al: Diurnal variation of plasma atrial natriuretic peptide in normals and patients with enuresis nocturna. Scand J Clin Lab Invest 1991; 51: 209. 6. Vurgun N, Yiditodlu MR, Ypcan A et al: Hypernatriuria and kaliuresis in enuretic children and the diurnal variation. J Urol 1998; 159: 1333. 7. Aceto G, Penza R, Coccioli MS et al: Enuresis subtypes based on nocturnal hypercalciuria: a multicenter study. J Urol 2003; 170: 1670. 8. Kamperis K, Rittig S, Jørgensen KA et al: Nocturnal polyuria in monosymptomatic nocturnal enuresis refractory to desmopressin treatment. Am J Physiol Renal Physiol 2006; 291: F1232. 9. Rittig S, Matthiesen TB, Pedersen EB et al: Sodium regulating hormones in enuresis. Scand J Urol Nephrol Suppl 1999; 202: 45. 10. De Guchtenaere A, Vande Walle C, Van Sintjan P et al: Nocturnal polyuria is related to absent circadian rhythm of glomerular filtration rate. J Urol 2007; 178: 2626.

11. Littlewood JM, Lee MR and Meadow SR: Treatment of childhood Bartter’s syndrome with indomethacin. Lancet 1976; 2: 795. 12. Natochin YV and Kuznetsova AA: Nocturnal enuresis: correction of renal function by desmopressin and diclofenac. Pediatr Nephrol 2000; 14: 42. 13. Sener F, Hasanoglu E and Soylemezoglu O: Desmopressin versus indomethacin treatment in primary nocturnal enuresis and the role of prostaglandins. Urology 1998; 52: 878. 14. Varan B, Saatci U, Ozen S et al: Efficacy of oxybutynin, pseudoephedrine and indomethacin in the treatment of primary nocturnal enuresis. Turk J Pediatr 1996; 38: 155. 15. Al Waili NS: Indomethacin suppository to treat primary nocturnal enuresis: double-blind study. J Urol 1989; 142: 1290. 16. Medel R, Dieguez S, Brindo M et al: Monosymptomatic primary enuresis: differences between patients responding or not responding to oral desmopressin. Br J Urol, suppl., 1998; 81: 46. 17. Thomassen AR, Bagger JP, Nielsen TT et al: Atrial natriuretic peptide during pacing in controls and patients with coronary arterial disease. Int J Cardiol 1987; 17: 267. 18. Kappelgaard AM, Nielsen MD and Giese J: Measurement of angiotensin II in human plasma: technical modifications and practical experience. Clin Chim Acta 1976; 67: 299. 19. Raes A, Dehoorne J, Van Laecke E et al: Partial response to intranasal desmopressin in children with monosymptomatic nocturnal enuresis is related to persistent nocturnal polyuria on wet nights. J Urol 2007; 178: 1048. 20. Vande Walle J, Vande Walle C, Van Sintjan P et al: Nocturnal polyuria is related to 24-hour diuresis and osmotic excretion in an enuresis population referred to a tertiary center. J Urol 2007; 178: 2630.

21. Kuznetsova AA, Shakhmatova EI, Prutskova NP et al: Possible role of prostaglandins in pathogenesis of nocturnal enuresis in children. Scand J Urol Nephrol 2000; 34: 27. 22. Batislam E, Nuhoglu B, Peskircioglu L et al: A prostaglandin synthesis inhibitor, diclofenac sodium in the treatment of primary nocturnal enuresis. Acta Urol Belg 1995; 63: 35. 23. Gelotte CK, Prior MJ and Gu J: A randomized, placebo-controlled, exploratory trial of ibuprofen and pseudoephedrine in the treatment of primary nocturnal enuresis in children. Clin Pediatr (Phila) 2009; 48: 410. 24. Fine LG and Trizna W: Influence of prostaglandins on sodium transport of isolated medullary nephron segments. Am J Physiol 1977; 232: F383. 25. Sakairi Y, Jacobson HR, Noland TD et al: Luminal prostaglandin E receptors regulate salt and water transport in rabbit cortical collecting duct. Am J Physiol 1995; 269: F257. 26. Agnoli GC, Borgatti R, Cacciari M et al: Renal function and urinary prostanoid excretions in saltdepleted women: comparative effects of enalapril and indomethacin treatments. Prostaglandins Leukot Essent Fatty Acids 1999; 60: 87. 27. Al Waili NS: Increased urinary nitrite excretion in primary enuresis: effects of indomethacin treatment on urinary and serum osmolality and electrolytes, urinary volumes and nitrite excretion. BJU Int 2002; 90: 294. 28. Baer JE, Hucker HB and Duggan DE: Bioavailability of indomethacin in man. Ann Clin Res, suppl., 1974; 6: 44. 29. Anderson RJ, Berl T, McDonald KD et al: Evidence for an in vivo antagonism between vasopressin and prostaglandin in the mammalian kidney. J Clin Invest 1975; 56: 420. 30. Sands JM: Regulation of renal urea transporters. J Am Soc Nephrol 1999; 10: 635.

EDITORIAL COMMENT Desmopressin was introduced more than 30 years ago as a practical treatment for monosymptomatic nocturnal enuresis.1 The agent benefits many patients who fail to achieve a normal diurnal surge of dDAVP. How-

ever, there are still patients with nocturnal polyuria who do not have a sustained response. Inhibition of cyclooxygenase has been linked to antidiuretic properties (reference 5 in article). Ear-

INDOMETHACIN IN PATIENTS WITH NOCTURNAL ENURESIS AND POLYURIA

lier attempts to quantify this effect were compromised by the lack of a homogeneous test population. The authors attempt to solve this problem by selecting a group of patients with demonstrated nocturnal polyuria and a failure to respond to conventional dDAVP treatment. If cyclooxygenase inhibition is effective, it could be a treatment for patients with recalcitrant MNE. The failure of some subjects to experience a pretreatment wet night raises ques-

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tions again about the study population. While there are still uncertainties, this avenue of research gives hope for these otherwise hard to treat patients. Julian Wan Division of Pediatric Urology Department of Urology University of Michigan Medical School Ann Arbor, Michigan

REFERENCE 1. Vande Walle J, Stockner M, Raes A et al: Desmopressin 30 years in clinical use: a safety review. Curr Drug Saf 2007; 2: 232.