Alpha1-antitrypsin gene polymorphisms are not associated with renal arterial fibromuscular dysplasia.

OBJECTIVE: We previously showed that fibromuscular dysplasia (FMD) of the renal artery may be familial. Case reports have associated alpha1-antitrypsin deficiency and FMD. The aim of this study was to test the implication of the alpha1-antitrypsin (AAT) gene in a large cohort of patients with renal FMD. MATERIALS AND METHODS: A case-control study comparing the genotype frequencies in 161 consecutive patients with angiographically proven renal FMD with those observed in three sets of controls (353 hypertensive patients, 288 normotensive patients, 444 normotensive women) was conducted. High-resolution echotracking of the carotid and radial arteries was performed in a subset of 77 FMD patients. Three functional polymorphisms of the AAT gene (PiM1, PiZ, PiS) were investigated. RESULTS: Clinical (age 44.3 +/- 13.8 years, 85.1% women) and radiological (77.1% of multifocal lesions) characteristics of the FMD population were consistent with those previously published. No differences were found in AAT genotype frequencies in the FMD subjects compared with the 1085 controls. We found no correlation between the AAT genotypes and the clinical and angiographical characteristics of the FMD patients. Echotracking results confirmed our previously published results in FMD patients with a specific pattern and a mean arterial phenotypic score greater than 3. However, no difference in the arterial score was observed across the genotypes. CONCLUSION: Polymorphisms PiM1, PiZ and PiS of the AAT gene are not associated with renal FMD or infraclinical carotid lesions detected by echotracking methods. As the true prevalence of renal FMD is not precisely known and alpha1-antitrypsin deficiency is not infrequent in the general population, the association of the two may occur by chance.

Evidence for carotid and radial artery wall subclinical lesions in renal fibromuscular dysplasia.

BACKGROUND: Fibromuscular dysplasia (FD) is a non-atherosclerotic, non-inflammatory arterial disease of unknown cause, and most frequently affects the renal and internal carotid arteries. Our objectives were to determine whether quantitative and qualitative lesions could be detected by high-resolution echotracking techniques at two arterial sites generally considered as free of echographic lesions: the common carotid and the radial arteries, and to compare their frequency with a control population. METHODS AND RESULTS: We studied 70 patients with renal FD and 70 control subjects matched for age, sex and systolic blood pressure. Arterial parameters were determined using non-invasive high-resolution echotracking systems. Carotid B-mode scans and radiofrequency signals were analysed and quoted by three observers blinded to diagnosis. FD patients had thicker carotid (+12%, P < 0.001) and radial arteries (+10%, P < 0.05) than controls. Abnormal echographic patterns of the carotid artery, including supernumerary interfaces and/or interruption of the blood-intima acoustic interfaces, were frequently observed in FD patients and rarely in control subjects. These abnormalities were quantified with a phenotypic score ranging from 2 to 7, and their sensitivity and specificity were 73 and 81%, respectively, as markers of FD. Having a phenotypic score > 3 conferred an odds ratio of 12.9 (95% CI 5.7-29.3) of having renal FD. CONCLUSION: We defined a new carotid phenotype in FD patients using a non-invasive echotracking system, and showed an increased wall thickness and distensibility of the radial artery. These data indicate the presence of subclinical lesions at arterial sites distant from the renal arteries, suggesting that renal FD is not a focal but a systemic arterial disease.

Apparent mineralocorticoid excess: report of six new cases and extensive personal experience.

In mineralocorticoid target tissues such as the cortical collecting duct in the kidney, the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) is responsible for the peripheral inactivation of cortisol to cortisone, thereby protecting the mineralocorticoid receptor from inappropriate activation by cortisol. Mutations in the HSD11B2 gene cause the syndrome of apparent mineralocorticoid excess, an autosomal recessive form of inherited hypertension in which cortisol acts as a potent mineralocorticoid. Herein are described six new families with mutations in the HSD11B2 gene causing hypokalemic hypertension, with low plasma aldosterone and low renin levels in affected individuals, indicating mineralocorticoid hypertension. Profiling of urinary steroid metabolites showed decreased cortisol inactivation, with urinary tetrahydrocortisol and tetrahydrocortisone ratio (THF + 5alphaTHF)/THE ranging 2.4 to 40 and nearly absent urinary free cortisone in all but one case. Genetic analysis of the HSD11B2 gene from these patients with apparent mineralocorticoid excess revealed distinct homozygous point mutations in four families, a compound heterozygous mutation in one family, and a large 23-bp exonic insert with frameshift and disruption of the amino acid sequence in another family. Expression studies of mutants that were expressed in HEK-293 cells showed marked reduction or abolition of 11betaHSD2 enzymatic activity. These cases are reviewed along with previous ones from the authors' extensive personal experience to highlight the importance of 11betaHSD2 in the understanding of a new biologic principle in hormone action, demonstrating that local metabolism of the glucocorticoid hormones into inactive derivatives by the enzyme 11betaHSD2 is one of the mechanisms that intervene to allow specific aldosterone regulatory effects.