Role of 11βHSD Type 2 Enzyme Activity in Essential Hypertension and Children with Chronic Kidney Disease (CKD)

Background: The mineralocorticoid receptor is protected from excess of glucocorticoids by conversion of active cortisol to inactive cortisone by enzyme 11 beta-hydroxysteroid dehydrogenase type 2 present in the kidney. The metabolites of cortisol and cortisone are excreted in the urine as tetrahydrocortisol (5 alpha THF + 5 beta THF) and tetrahydrocortisone (THE), respectively. Hypothesis: Patients with chronic kidney disease (CKD) and essential hypertension have a functional defect in their ability to convert cortisol to cortisone, thus leading to the activation of mineralocorticoid receptor. Objective: The objective of the investigation was to study the ratio of urinary steroids (5 alpha THF + 5 beta THF) to THE in patients with CKD, postrenal transplant, and essential hypertension and to compare the ratio with controls. Design/Methods: We enrolled 44 patients (17 with CKD, eight postrenal transplant, 19 with essential hypertension) and 12 controls. We measured spot urinary 5 alpha-THF, 5 beta-THF, THE, free active cortisol and inactive cortisone by gas chromatography/mass spectrometry. We collected data on age, sex, cause of kidney disease, height, weight, body mass index, blood pressure, serum electrolytes, aldosterone, and plasma renin activity. Blood pressure percentiles and z-scores were calculated. The glomerular filtration rate was calculated using the modified Schwartz formula. Results: The ratios of 5 alpha THF + 5 beta THF to THE were significantly higher in patients with CKD [mean +/- SD score (SDS) = 1.31 +/- 1.07] as compared with essential hypertension (mean +/- SDS = 0.59 +/- 0.23; P = 0.02) and controls (mean +/- SDS = 0.52 +/- 0.25; P = 0.01). In the postrenal transplant group, the ratio was not significantly different (mean +/- SDS = 0.71 +/- 0.55). The urinary free cortisol to free cortisone ratios were significantly higher in the hypertension and CKD groups as compared with the controls. The 5 alpha THF + 5 beta THF to THE ratio negatively correlated with the glomerular filtration rate and positively correlated with systolic and diastolic blood pressure z-scores. The correlation of the blood pressure z-scores with ratios was stronger in the CKD group than the essential hypertension and posttransplant groups. Conclusions: We have elucidated a functional deficiency of 11 beta-hydroxysteroid dehydrogenase type 2 in children with CKD and a subset of essential hypertension. Urinary 5 alpha-THF, 5 beta-THF, and THE analysis by gas chromatography/mass spectrometry should be a part of routine work-up of CKD and hypertensive patients. (J Clin Endocrinol Metab 97: 3622-3629, 2012)