ABSTRACT

Second only to asthma in terms of prevalence, bedwetting (enuresis nocturna) affects 7-10% of 7-year-old children and persists into adulthood to a considerable degree. Although benign in its nature, bedwetting can lead to considerable emotional instability. The excretion of large amounts of urine at night (nocturnal polyuria) is a major aetiological factor in nocturnal enuresis. An abnormal diurnal rhythm in vasopressin synthesis that is easily corrected with the synthetic vasopressin analogue dDAVP has been identified in enuretics with nocturnal polyuria. However, a subgroup of enuretics presents with nocturnal polyuria refractory to dDAVP.

The aim of the present PhD dissertation was to evaluate the normal circadian variations in urine output and composition in healthy children and the physiological mechanisms responsible for the dDAVP resistant nocturnal polyuria seen in a subgroup of enuretics. Furthermore, we assess the effect of dDAVP and indomethacin on renal water and solute handling in enuretics with nocturnal polyuria and controls.

Circadian variations in urine output and electrolyte excretion are evident in healthy children between the ages of three and 14 years. The reductions in the amount of urine and solutes excreted during the night correlate with analogous reductions in the amount of prostaglandin E2 excreted. Furthermore, we demonstrate that children with nocturnal enuresis and dDAVP resistant nocturnal polyuria excrete larger amounts of salt and other solutes at night compared to controls. Sodium regulating hormones of the renin angiotensin aldosterone system and atrial natriuretic peptide are not responsible for the enuresis related natriuresis which instead seems attributable to an increased nocturnal prostaglandin E2 excretion.

Children with nocturnal enuresis and nocturnal polyuria showing no response to dDAVP at home, respond well to the agent when given during hospitalization and under standardized conditions. Apart from the well-described effect of dDAVP on free water clearance we document a marked effect on the amount of sodium and urea excreted. This is most likely a direct effect of dDAVP on renal tubules as neither sodium regulating hormones nor renal prostaglandins are influenced by the agent. Indomethacin being a potent cyclooxygenase inhibitor has antinatriuretic properties in both enuretics with nocturnal polyuria and controls. Despite this, indomethacin does not seem to reduce the nocturnal urine output in children with nocturnal polyuria to the same extent as dDAVP.

Our results point towards several areas of interest for further research such as the relation between dDAVP bioavailability and clinical effect, the mechanisms responsible for excess nocturnal sodium excretion and prostaglandin overproduction seen in selected populations of enuretics and the role of prostaglandin inhibition as a therapeutic alternative in children with enuresis nocturna.