Glycyrrhetinic Acid Food Supplementation Lowers Serum Potassium Concentration in Chronic Hemodialysis Patients

Stefan Farese; Anja Kruse; Andreas Pasch; Bernhard Dick; Brigitte M Frey; Dominik E Uehlinger; Felix J Frey


Kidney Int. 2009;76(8):877-884. 

In This Article

Abstract and Introduction


Hyperkalemia is a common life-threatening problem in hemodialysis patients. Because glycyrrhetinic acid (GA) inhibits the enzyme 11β-hydroxy-steroid dehydrogenase II and thereby increases cortisol availability to the colonic mineralocorticoid receptor, it has the potential to lower serum potassium concentrations. To test this, 10 patients in a 6 month prospective, double-blind, placebo-controlled crossover study were given cookies or bread rolls supplemented with glycyrrhetinic acid or placebo. Twenty-four-hour blood pressure measurements were performed at baseline and week 6 and 12 of each treatment period. The ratio of plasma cortisol/cortisone was significantly increased in all patients on GA as compared to baseline or placebo, indicating appropriate enzyme inhibition. Nine of the 10 patients had a persistent decrease in predialysis serum potassium concentration. On GA, mean predialysis serum potassium was significantly lower than at baseline or on placebo. On placebo, serum potassium was significantly elevated above the upper limit of normal in 76% compared to 30% of measurements during GA treatment. Furthermore, on this treatment the frequency of severe hyperkalemia significantly decreased from 9% to 0.6%. No differences were found in parameters reflecting sodium retention. Although these studies show that prolonged GA supplementation persistently lowers serum potassium in dialysis patients, a long-term toxicity study will be mandatory before we recommend the routine use of this treatment.


Hyperkalemia is a common and sometimes life-threatening problem in patients with end-stage renal disease and is a frequent reason for emergency dialysis in patients undergoing chronic renal replacement therapy.[1] Severe hyperkalemia (serum potassium > 6.0 mmol/l) was reported to occur in up to 12%[2–4] of hemodialysis patients. In these patients, three mechanisms account for hyperkalemia: an increase in potassium intake, a decreased potassium excretion and a shift of intracellular potassium to the extracellular fluid. Metabolic acidosis, the main mechanism for intra–extracellular potassium shift, is not a relevant cause of hyperkalemia at steady state in adequately dialysed patients. The efficacy of a dietary restriction of potassium intake as a measure to avoid hyperkalemia is often limited for nutritional and compliance reasons.[1] In patients without renal function, the gastrointestinal excretion of potassium has a pivotal role.[3,5] Thus, pharmacological interventions enhancing the gastrointestinal excretion of potassium are of potential relevance. The gastrointestinal mode of disposal of potassium is enhanced by cation exchange resins, together with a cathartic, usually sorbitol.[6] The efficacy of the unpleasant resin therapy has been questioned[7] and gastrointestinal side effects, including colonic necrosis, have been observed.[8,9] Thus, alternative agents to enhance gastrointestinal potassium removal are warranted.

Potassium secretion is an established mechanism of rectal and colonic mucosa.[10,11] This loss is regulated, at least in part, by the mineralocorticoid receptor (MR).[12] The activation of the MR by fludrocortisone enhances the rectal electrical potential difference, an effect that is mimicked by inhibiting the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD2) in segments of normal rectal colon obtained from humans.[13]

The 11β-HSD2 enzyme converts endogenous cortisol into cortisone in mineralocorticoid target tissues including epithelial cells of the colon.[14,15] This mechanism protects the MR from promiscuous activation by cortisol (Figure 1).[16–18] Therefore, we hypothesize that inhibition of 11β-HSD2 might enhance intestinal potassium loss. In a 2-week preliminary proof of principle study, we showed that inhibition of 11β-HSD2 by glycyrrhetinic acid (GA), the active ingredient of licorice, decreased serum potassium concentrations in patients on dialysis,[19] an observation suggesting that this xenobiotic has the potential to be a potassium-lowering agent in dialysis patients. To determine the efficacy and safety of GA, we designed a trial with a 3-month treatment period and a 3-month placebo period.

Figure 1.

Glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) are ligand-inducible transcription factors. Following binding of steroid hormones these receptors translocate from the cytoplasm into the nucleus and display their transactivation potential. The intracellular concentrations of steroid molecules available for binding to the cognate receptor depends on the free extracellular concentrations and an intracellular prereceptor control mechanism constituted by the 11 β-hydroxyglucocorticoid dehydrogenase (11 β-HSD) enzyme. The 11β-HSD2 enzyme acts predominantly as a dehydrogenase and converts 11β-hydroxyglucocorticoid cortisol with a high affinity for both GR and MR into 11-ketosteroid cortisone with virtually no affinity for MR or GR. By this mechanism the 11β-HSD2 enzyme protects MR from promiscuous activation by the glucocorticoid hormone cortisol. Inhibition of the 11β-HSD2 enzyme by glycyrrhetinic acid (GA) increases cortisol concentrations in MR-expressing cells and therefore causes a glucocorticoid-mediated mineralocorticoid effect (from refs. 18 and 49).