Type I pseudohypoaldosteronism (PHA) is a hereditary syndrome of
salt wasting resulting from unresponsiveness to
mineralocorticoids. PHA is manifested in two clinically and genetically distinct forms, affecting either only the kidney or multiple target organs of
aldosterone. We examined the
mineralocorticoid effect of
carbenoxolone (CBX) in young PHA patients with either renal or multisystem resistance to
aldosterone to find out whether CBX may help reduce the requirement for a high-
salt diet. CBX did not show any significant
salt-retaining effect in two patients with multiple PHA, and did not affect the
renin-
aldosterone system. In contrast, CBX significantly suppressed the
renin-
aldosterone system in a renal PHA patient for the whole
duration of treatment, but without a long-term
salt-retaining effect. On CBX treatment, urinary
cortisone levels decreased and the
cortisol:
cortisone ratio increased, indicating that CBX inhibited 11beta-HSD activity that metabolizes
cortisol to
cortisone. The complete lack of effect of CBX on the
renin-
aldosterone system in multisystem PHA patients indicates that CBX does not exert an effect via
mineralocorticoid (MR) or
glucocorticoid receptors. Examination of the structure and expression of the MR gene by Southern blot analysis and polymerase chain reaction (PCR) showed no abnormality. Whereas multiple PHA results from a spectrum of mutations in the
mineralocorticoid activated
epithelial sodium channel subunits, the genetic basis of renal PHA is still unknown. The response to CBX suggests that there is at least a partly functional MR in renal PHA patients.