Role of 11ßHSD 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 11ß-hydroxysteroid dehydrogenase type 2 present in the kidney. The metabolites of cortisol and cortisone are excreted in the urine as tetrahydrocortisol (5αTHF+5ßTHF) 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 (5αTHF+5ßTHF) 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 5α-THF, 5ß-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 5αTHF+5ßTHF 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 5αTHF+5ßTHF 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 11ß-hydroxysteroid dehydrogenase type 2 in children with CKD and a subset of essential hypertension. Urinary 5α-THF, 5ß-THF, and THE analysis by gas chromatography/mass spectrometry should be a part of routine work-up of CKD and hypertensive patients.

Evaluation of arterial structure and function in pediatric patients with end-stage renal disease on dialysis and after renal transplantation.

CVD is a major cause of morbidity and mortality in pediatric patients with CKD. It is unclear whether vascular abnormalities in these patients are reversible, and if transplantation portends salutary effects on arterial function. We compared FMD, PWV, AI75, and CIMT in 15 dialysis (D), 14 transplant patients (T), and 15 controls (C), and their associations with cardiovascular risk factors. There was stepwise lower FMD (p < 0.001), higher AI75 (p < 0.001), higher PWV (p = 0.01), and higher CIMT SDS for age (p = 0.03) and height (p = 0.006) in the D group than T and C groups. FMD, PWV, and CIMT were unrelated to dialysis duration or time from transplantation. On multivariate analysis, group status was independently associated with FMD (ß = 3.15, p = 0.002), AI75 (ß = -5.95, p = 0.01), PWV (ß = -0.57, p = 0.07) and CIMT (ß = -0.02, p = 0.04) and CIMT SDS for height (ß = -0.541, p = 0.009). FMD is lower and AI75, PWV and CIMT are higher in pediatric patients maintained on D than T/C. T patients have similar AI75, PWV and CIMT to C although FMD remains reduced. These findings suggest that transplantation stabilizes or improves CKD associated arteriopathy.

A novel mutation in the complement factor B gene (CFB) and atypical hemolytic uremic syndrome.

We report the case of an 8-year-old girl diagnosed with atypical hemolytic uremic syndrome (aHUS) with a complement factor B (CFB) gene mutation. aHUS is a disease of complement dysregulation. In approximately 50% of patients, mutations are identified in genes encoding regulators of complement-complement factor H (CFH), membrane cofactor protein or complement factor I (CFI)-or activators of complement-complement factor B (CFB) or C3. The mutation in this patient was identified in exon 12 of CFB and changes a lysine at amino acid position 533 to an arginine (c.1598A>G p.Lys533Arg). The two other mutations previously reported in CFB associated with aHUS are c.858C>G, p.F286L in exon 6 and c.967A>Gp.K323E in exon 7.