Does kidney transplantation normalise cortisol metabolism in apparent mineralocorticoid excess syndrome?

The syndrome of apparent mineralocorticoid syndrome (AME) results from defe ctive 11 beta-hydroxysteroid dehydrogenase 2 (11 beta-HSD2). This enzyme is co-expressed with the mineralocorticoid receptor (MR) in the kidney and co nverts cortisol to its inactive metabolite cortisone. Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, su ppression of PRA and hypertension. Thus, the syndrome is a disorder of the kidney. We present here the first patient affected by AME cured by kidney t ransplantation. Formerly, she was considered to have a mild form of the syn drome (Type II), but progressively she developed renal failure which requir ed dialysis and subsequent kidney transplantation. To test the ability of t he transplanted kidney to normalise the patient's cortisol metabolism, we g ave, in two different experiments, 25 and 50 mg/day of cortisone acetate or 15 and 30 mg/day of cortisol after inhibition of the endogenous cortisol b y synthetic glucocorticoid (methylprednisolone and dexamethasone). The AME diagnostic urinary steroid ratios tetrahydrocortisol+5 alpha tetrahydrocort isol/tetrahydrocortisone and cortisol/cortisone were measured by gas chroma tography/mass spectrometry. Transplantation resulted in lowering blood pres sure and in normalization of serum K and PRA, After administration of a phy siological dose of cortisol (15 mg/day), the urinary free cortisol/cortison e ratio was corrected (in contrast to the A-ring reduced metabolites ratio) , confirming that the new kidney had functional 11 beta-HSD2. This ratio wa s abnormally high when the supra-physiological dose of cortisol 30 mg/day w as given. After cortisone administration, the tetrahydrocortisol+5 alpha te trahydrocortisol/tetrahydrocortisone ratio resulted normalised with both ph ysiological and supra-physiological doses, confirming that the hepatic redu ctase activity is not affected. As expected, the urinary free cortisol/cort isone ratio was normal with physiological, but increased after supra-physio logical doses of cortisone. The described case indicates a normalisation of cortisol metabolism after kidney transplantation in AME patient and confir ms the supposed pathophysiology of the syndrome. Moreover, it suggests a ne w therapeutic strategy in particularly vulnerable cohorts of patients inade quately responsive to drug therapy or with kidney failure. (C) 2000, Editri ce Kurtis.