Pathophysiological aspects of nocturnal polyuria in healthy elderly volunteers: An explorative study of the pharmacokinetics and

An explorative study of the pharmacokinetics and
the effects of dDAVP on renal water and solute excretion

This PhD dissertation was accepted by the Faculty of Health Sciences of the University of Aarhus, and defended on October 31, 2003.

Official opponents: Thomas En Jonassen, Anders Matiasson, Sweden, and Hans Ørskov.

Tutors: Jens Christian Djurhuus, Jørgen Frøkiær, and Søren Nielsen.

Correspondence to: Gitte M. Hvistendahl, Odinsvej 4, DK-8230 Åbyhøj.

Dan Med Bull 2004;51:135.

ABSTRACT

The study was carried out at the Institute of Experimental Clinical Research, the Water and Salt Centre, Aarhus University, and the department of Urology, Skejby Sygehus, Aarhus, Denmark. Nocturia is a very common symptom in elderly persons and quality of life decreases significantly in many nocturics as a consequence of disrupted sleep, impaired productivity and daytime fatigue. In many elderly subjects nocturia is caused by a large nocturnal urine output (nocturnal polyuria) and often the nocturnal polyuria has no underlying disease that explains the changed circadian rhythm in urine output. Age-related alterations in the renal concentrating mechanisms are evident, but the exact hormonal or intra-renal changes are still obscure.

Pharmacokinetic, pharmakodynamic and safety parameters of desmopressin (dDAVP) treatment were studied in elderly nocturics. A single blood sample +2 hours post dose was sufficient to predict the pharmacokinetic profile. There seemed to be a relationship between sex, absorption level of dDAVP and the incidence of adverse events as the absorption was significantly higher in elderly women compared to elderly men. The nocturnal diuresis and the number of nocturnal voids were approximately halved on dDAVP.

The age-related changes in urine output and solute excretion were studied in elderly nocturnal polyurics, elderly nocturnal non-polyurics and in young controls. The elderly nocturnal polyurics had an inversed diurnal variation in urine output, urine osmolality, urinary sodium excretion and urinary AQP2 concentration. In the elderly nocturnal polyurics the circadian rhythm of AVP was absent. Generally, the elderly had higher ANP secretion than the young controls, but the elderly nocturnal polyurics demonstrated the highest nocturnal levels, which may explain the nocturnal natriuresis observed in this group. After a single test dose of dDAVP the inversed diurnal variation was changed to normal in the elderly nocturnal polyurics resembling the pattern seen in the elderly nocturnal non-polyurics. Interestingly, the compensatory diuresis following anti-diuresis was postponed compared to the young controls indicating a longer duration of action of dDAVP in the elderly participants. The nocturnal urine AQP2 concentration was correlated to both the nocturnal diuresis and the nocturnal osmolality.

A new method for detection of BSC-1 and TSC in humane urine was introduced. A clear, but insignificant, increase in nocturnal urine BSC-1 after dDAVP was observed in the elderly nocturnal polyurics suggesting a possible association between urinary sodium excretion and urinary BSC-1.

dDAVP may be a possible treatment modality in nocturnal polyuria. The detection of AQP2 and Na-transporters in urine samples may be of importance in diagnosing and monitoring different conditions with disturbances of the renal concentrating mechanisms.