Increased cortisol metabolites and reduced activity of 11β-hydroxysteroid dehydrogenase in patients on hemodialysis

Abstract

Background. Patients with renal failure have symptoms assumed to be attributable to the accumulation of toxic endo- or xenobiotics. Most of these molecules, especially those with a molecular weight >300 D, have not been identified. In addition to excretion, the kidney is involved in some defined metabolic processes. In the cortical collecting duct, the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) interconverts cortisol (F) and cortisone (E), and the metabolites of these glucocorticoids, tetrahydrocortisol (THF), 5α-tetrahydrocortisol (5α-THF) and tetrahydrocortisone (THE), are excreted in urine. We hypothesized that first, these metabolites accumulate and second, their concentration pattern changes in patients on hemodialysis. Methods. THF, 5α-THF, THE, F and E were measured in plasma of 63 patients on dialysis and in 34 healthy controls by gas-chromatography-mass spectrometry (GC/MS). In 11 patients, the metabolite clearance was determined during high flux hemodialysis by using a population pharmacokinetic approach. Results. Mean plasma concentrations of THF, 5α-THF and THE were more than five times higher and those of E lower in patients than in controls. The ratios of (THF + 5α-THF)/THE and F/E were increased in patients, indicating a reduced activity of 11β-HSD2. Intradialytic clearances were between 120 and 300 mL/min and not sufficient to normalize the steroid concentrations. Conclusion. Patients on hemodialysis exhibit pronounced increases in THF, 5α-THF and THE concentrations in plasma with insufficient removal during dialysis. Due to a reduced 11β-HSD2 activity, an abnormal pattern of the concentrations of these cortisol and cortisone metabolites is observed. Since many signs and symptoms in uremic patients resemble those observed in subjects with glucocorticoid excess, the clinical relevance of the high concentrations of these glucocorticoid metabolites deserves further investigation.