Fibromuscular dysplasia of the renal arteries: studies on aetiology

The focus of this thesis is the aetiology of renal arterial fibromuscular dysplasia (FMD), a non-atheromatous, non-inflammatory disease of blood vessels, which predominantly affects medium-sized arteries. An extensive review of the literature was undertaken to summarise the current state of knowledge regarding renal arterial FMD, and to identify and critically examine already proposed aetiological and pathogenic factors. Medial fibroplasia, the most common form of FMD, is characterised by the typical "string of beads" (or multifocal) angiographic appearance. It predominantly affects females of reproductive age, usually affects the right renal artery or is bilateral, and may be familial. Female hormonal influences are likely to play a role, as suggested by the female predominance and experimental evidence of estrogenic effects on vascular smooth muscle cells and on endothelial function. Mechanical stretching due to haemodynamic forces and/or traction from the attached kidney is also a plausible factor. However, neither of these appears to be a sufficient explanation. Ninety-two subjects with renal arterial FMD were recruited from a group of 110 patients with renal arterial FMD treated at the Hypertension Unit, Greenslopes Hospital. Each subject was interviewed and, where possible (in 55 subjects) examined. Venous blood was obtained from 83 subjects. The clinical and demographic characteristics of this cohort were similar to cohorts previously described in the literature, and included two instances of familial occurrence of multifocal FMD. Coexistent primary aldosteronism was diagnosed in eight patients, highlighting the necessity for careful evaluation of the cause of hypertension in patients found to have renal arterial FMD. The relationship between smoking and severity of FMD was examined in a group of 50 subjects (24 smokers) with the multifocal FMD. At the time of diagnosis of FMD, smokers were of younger mean age than non-smokers (38.7 years vs 48.9 years, p < 0.01), had a shorter median history of hypertension (1.5 years vs 8.5 years, P < 0.05), and had a higher prevalence of unilateral renal atrophy (67% vs 27%, P < 0.01). The distribution of age at diagnosis of FMD was unimodal in non-smokers and bimodal, with a discrete group of younger subjects, in smokers. These findings are consistent with cigarette smoking being associated with an earlier onset and increased severity of disease in a susceptible subgroup of patients predisposed to multifocal FMD. To further investigate a proposed association between α1-antitrypsin deficiency and FMD, α1-antitrypsin phenotyping was performed by isoelectric focusing (+/- genotyping) in 83 patients with renal arterial FMD. The phenotype distribution and allele frequencies were similar to those reported for normal subjects from two Australian populations, suggesting that α1-antitrypsin deficiency is not a common aetiological factor in renal arterial FMD. However, two patients from the present series together with nine culled from the literature suggest that the chance combination of α1-antitrypsin deficiency and FMD may predispose to severe manifestations of FMD. Examination of polymorphisms by PCR for angiotensin-converting enzyme (ACE) I/D, angiotensin II type 1 receptor (AT1R) A1166C and angiotensinogen (AGT) M235T and T174M was undertaken in 43 patients with typical multifocal FMD (MFFMD) and in 89 controls. Allele frequencies did not differ significantly between groups, except that MF-FMD patients had a significantly higher frequency of the ACE I allele than control subjects (0.62 vs. 0.47, p = 0.026). Since the ACE I allele is associated with lower circulating ACE levels and possibly lower tissue levels of angiotensin II (Ang II), and since Ang II modulates vascular smooth muscle cell growth and synthetic activity, the I allele might predispose to defective remodeling of the arterial media, and thus to the development of MF-FMD. The 4a/b polymorphism in intron 4 and the Glu298Asp (G894T) polymorphism in exon 7 of the endothelial nitric oxide synthase gene were also examined. No statistically significant association was found between MF-FMD and alleles of the ecN0S4a/b or ecNOS G894T polymorphisms. The studies presented in this thesis have identified and explored some possible aetiologic and pathogenic factors in renal arterial FMD. Further evidence has been presented for the detrimental effects of cigarette smoking. The possible association between α1-antitrypsin deficiency and FMD has been clarified. A possible role for the ACE I/D polymorphism has been identified. Much more remains to be discovered about renal arterial FMD, including genetic influences, and recommendations for future research have been presented.