The finding helps physiologists understand why about 30% of children who suffer from bedwetting (nocturnal enuresis) do not respond to desmopressin, a drug that successfully treats the other 70%. The findings, made by Danish medical doctors who treat enuresis, could help lead to better treatment for these children.

The study "Nocturnal polyuria in monosymptomatic nocturnal enuresis refractory to desmopressin treatment," was carried out by Konstantinos Kamperis and Jens Christian Djurhuus of the University of Aarhus, Aarhus, Denmark and Soren Rittig and Kaj Anker Jorgensen of the Aarhus University Hospital. The study appears in the December issue of the American Journal of Physiology-Renal Physiology published by the American Physiological Society.

Circadian rhythm important

Urine output is controlled, in part, by our own internal daily clocks, or circadian rhythm. With the transition from day to night, our bodies reduce the amount of excreted water, electrolytes and other metabolic end products in preparation for hours of sleep. We are not born with this circadian rhythm, but it usually develops in early childhood.

Some children take longer to develop this rhythm, which is why about 15% of enuretic children will spontaneously stop bedwetting each year without any intervention or treatment. The condition affects 7-10 percent of 7-year-old children, but some severe cases linger much longer. As many as 2 percent of young adults have the problem, which may persist for life.

In a psychological sense, enuresis takes a severe toll, and is among the conditions children worry about most, Rittig said. When asked to imagine the worst things that could happen to them, children rated bedwetting in the top 10, he said.

Rittig published a study in 1989 showing that the hormone vasopressin plays a role in enuresis. This research helped lead to the use of desmopressin to stop bedwetting in many enuretic children. But he and others have remained puzzled as to why some children do not respond to desmopressin. In this study, the researchers set out to understand the physiological mechanisms behind the 30% of desmopressin nonresponders.

24-hour study

The researchers examined 46 enuretic children, ages 7-14, who were outpatients at the Center for Child Incontinence at Aarhus University Hospital and whose enuresis had failed to respond to desmopressin. The enuretic children were subdivided into a "polyuric" group (average nocturnal output on wet nights exceeded 130% of expected bladder capacity) and nonpolyuric (output on wet nights less than 130% of expected capacity). The study also included an age-matched control group of 15 non-enuretic children.

The children spent two nights at Aarhus University Hospital. The first night was to acclimate the children to the hospital environment while the second night was the experimental period. The researchers collected blood and urine from the children during the second night, without waking them. This gave the researchers a more complete picture of physiological changes that occur through the course of an entire night.

Fluid and sodium intake was standardized for all children, based on their weight, to eliminate the possibility that enuretic episodes were related either to excess sodium or fluid intake. All children had adequate bladder capacity and were healthy. None experienced daytime incontinence.

Some enuretic children (five polyurics and four nonpolyurics) did not have a wet night during their stay. This is not unusual for enuretic children, many of whom get through some nights without an episode. The enuretic children who were dry provided one more opportunity to find the physiological difference between them on dry and wet nights, Kamperis said.

Results implicate sodium

Circadian variations in urine output were evident for all groups. However, polyuric children excreted twice as much urine during the night, compared to the nonpolyuric children and the controls. The researchers found that the urine of the polyuric children who wet their beds during the experiment contained more:

• sodium
• urea
• prostaglandin

Interestingly, the children who wet the bed did not excrete a greater volume of water: It was the sodium and urea content that made the difference. Sodium and urea excretion was much higher among children who wet the bed, and these substances expand the volume of urine in the bladder, leading to enuresis.

The study also found that urine from enuretic episodes in the first hours of sleep is quite different from the urine the researchers collected in the morning. "When we look at what happens in the last hours of the night, we couldn't find any differences," Kamperis said. "The first hours are most important."

The study looked at a variety of other factors that could play a role in bedwetting, including mean arterial pressure, heart rate, atrial natriuretic peptide, angiotensin II, aldosterone and renin levels, but found no differences among the groups. Also, there was no difference in the amount of vasopressin between the two enuretic groups.

"We found enuresis-related polyuria to be largely due to an abnormal nocturnal renal handling of solutes and in particular, sodium," the authors wrote. While the study suggests that sodium is the main culprit among this subpopulation of enuretic children, there is much still to be done to understand how the process works.

The increased prostaglandin production of the polyurics could account for the difference in excretion of sodium, the authors noted. Prostaglandins counteract the actions of vasopressin and influence of how much sodium we excrete.

Next step: treatment trial

The researchers have begun treating children who do not respond to desmopressin with indomethacin, a prostaglandin inhibitor. Those trials, which include a placebo, are expected to be completed within a year, Rittig said.

This study was supported by grants from the University of Aarhus Research Foundation, Egmont Foundation and Karen Elise Jensen Foundation.

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