Pseudohypoaldosteronism due to renal and multisystem resistance to mineralocorticoids respond differently to carbenoxolone

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 11β-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.