Nicholas Daunt

Review: Diagnosis and management of primary aldosteronism

JRAAS 2001;2:156-69 Introduction Primary aldosteronism (PAL) is characterised by aldosterone production which is excessive to the body’s requirements and relatively autonomous of its normal chronic regulator, angiotensin II (Ang II). Inappropriate aldosterone production results in excessive reabsorption of sodium via the amiloride-sensitive epithelial sodium channels situated within the distal tubule and collecting duct of the kidney (leading to hypertension), and continues in the face of suppression of the reninangiotensin system (RAS). Urinary loss of potassium, which is exchanged for sodium at the distal nephron, may eventually result in hypokalaemia if severe and prolonged enough. Because measurements of plasma aldosterone and plasma renin activity (PRA) have become readily available, it is now feasible to measure their relationship in all hypertensive patients. The wide application of the aldosterone/PRA ratio (ARR) has permitted the diagnosis of PAL in the absence of hypokalaemia,and more commonly, in fact, than in the presence of hypokalaemia. This has led to a new understanding that PAL is not a rare cause of hypertension, to be suspected only when hypokalaemia is present, but is probably the commonest, identifiable, specifically treatable and potentially curable form of hypertension. With most recent studies reporting prevalence rates for PAL that are much higher than those previously described in medical textbooks and reviews on the subject, the diagnosis of PAL is likely to become an increasingly frequent event. The ability to correctly apply diagnostic techniques involved in the workup of PAL and to interpret their results therefore represent skills of increasing importance for physicians who treat hypertension. This review focuses on the rationale and methodology of these diagnostic techniques, and on current approaches to management of patients with PAL.

Impact of Different Diagnostic Criteria During Adrenal Vein Sampling on Reproducibility of Subtype Diagnosis in Patients With Primary Aldosteronism

In patients with primary aldosteronism, adrenal vein sampling (AVS) is considered the only reliable technique to distinguish between unilateral and bilateral autonomous production of aldosterone, but agreement is lacking on the best criteria indicating successful cannulation and lateralization. The objective of this study was to assess the impact of differing criteria for the successful cannulation and lateralization on the reproducibility of subtype diagnosis. Sixty-two patients with confirmed primary aldosteronism underwent AVS on 2 separate occasions, because the first was unsatisfactory. We compared the different diagnoses of primary aldosteronism subtype reached using AVS data assessed by permissive (type 1), intermediate (type 2), and strict (type 3) criteria. Although 91.1% of all of the (both first and second) AVSs were “successful” by type 1 criteria (50.8% by type 2 and 33.9% by type 3), in only 35.3% of patients was the diagnosis concordant between the first and second AVS. Type 1 criteria also led to a higher rate of diagnosis of unilateral primary aldosteronism (67.3% of successful procedures) than type 2 (36.5%) or type 3 (26.2%). There was considerable disparity in the diagnosis reached using the 3 different criteria, with concordance in only 32.2%. Using either type 1 or 2 criteria, the minimal adrenal/peripheral vein cortisol ratio necessary to obtain the same diagnosis in the first and second AVS procedures was ≥2.75. In conclusion, permissive criteria for successful cannulation and lateralization on AVS achieve poor diagnostic reproducibility and should be avoided.

Polymorphisms of the renin-angiotensin system in patients with multifocal renal arterial fibromuscular dysplasia

Fibromuscular dysplasia (FMD) is an important cause of renal artery stenosis, particularly in young females. Polymorphisms of the renin-angiotensin (RA) system have been implicated in the pathogenesis of hypertension and atherosclerotic vascular disease, and may play a role in the development 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 renal arterial FMD (MF-FMD) and in 89 controls. The age of MF-FMD patients at the time of diagnosis of hypertension did not differ (38.6 + 11.1 years vs 35.5 ± 10.3 years, P = 0.12) from controls and the proportion (95% vs 86%, P = 0.14) of females was similar. 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 remodelling of the arterial media, and thus to the development of MF-FMD. This contrasts with atherosclerotic renal artery stenosis, coronary stent restenosis and carotid intimal thickening, which are diseases affecting the arterial intima, and which are associated with increased frequency of the D allele.

Increased severity of multifocal renal arterial fibromuscular dysplasia in smokers

Renal arterial fibromuscular dysplasia (FMD) is a significant cause of renovascular hypertension, especially in younger females. Tobacco constituents have been shown to stimulate proliferation and synthetic activity of cultured human vascular smooth muscle cells. We examined the relationship between smoking and severity of FMD in a group of 50 subjects with the multifocal form of renal arterial FMD. A detailed smoking history was obtained by interview, clinical data at diagnosis of FMD were obtained from medical records, and angiograms were reviewed. Clinical and angiographic features were compared between smokers and non-smokers. Twenty-four subjects were smokers. 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. we conclude that cigarette smoking is associated with an earlier onset and increased severity of disease in a susceptible subgroup of patients predisposed to multifocal renal arterial fmd.

Alpha-1-antitrypsin phenotypes in patients with renal arterial fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a significant cause of renal artery stenosis, especially in young females. A rare association between FMD and α1-antitrypsin (α1-AT) deficiency has been reported. We compared the α1-AT phenotype distribution in 83 patients with renal arterial FMD with those published for Australian populations. α1-AT phenotyping was performed by isoelectric focusing between pH 4.2 and pH 4.9 on polyacrylamide gels with PiM1M2, PiFM (non-deficiency alleles), PiMS and PiMZ (deficiency alleles) markers. Following phenotyping, α1-AT genotyping was performed in 10 patients to confirm the presence of S and/or Z alleles. The phenotype distribution and allele frequencies were similar to those reported for normal subjects from two Australian populations (72 (86.7%) PiMM phenotype, one (1.2%) PiFM, seven (8.4%) PiMS, two (2.4%) PiMZ and one (1.2%) PiSZ), suggesting that α1-AT deficiency is not a common aetiological factor in renal arterial FMD. However, despite FMD being three times less common in males than females, and carotid artery dissection being a rare occurrence, a male with PiMS deficiency phenotype presented with internal carotid artery dissection and had bilateral renal artery FMD. Further, a patient with PiSZ deficiency phenotype was one of two sisters with FMD and was more severely affected than her PiMM normal phenotype sibling. These two patients from the present series together with nine culled from the literature with α1-AT deficiency phenotype and FMD suggest that the chance combination of α1-AT deficiency and FMD may predispose to severe manifestations of FMD.

Repeating adrenal vein sampling when neither aldosterone/cortisol ratio exceeds peripheral yields a high incidence of aldosterone-producing adenoma

Objectives: In primary aldosteronism, adrenal vein sampling (AVS) suggests unilateral aldosterone-producing adenoma (APA) when the aldosterone/cortisol (A/F) ratio is less than or equal to peripheral on one side and at least two times peripheral on the other. When A/F ratios are lower bilaterally than peripheral despite adequate samples (adrenal venous cortisol ≥3 times peripheral), we recommend repeat AVS. This study aimed to determine the frequency of this occurrence and outcomes in such cases. Methods: We performed a retrospective observational study of all cases of primary aldosteronism undergoing initial AVS over a 34-year period. Results: Initial AVS in 1397 patients returned satisfactory and discriminatory results in 1066 (76.3%) but 37 patients (2.6%) had adequate samples but bilateral A/F ratios no higher than peripheral. Of the 22 of these 37 who agreed to repeat AVS, 10 demonstrated unilateral aldosterone production, and eight of these had unilateral adrenalectomy disclosing APAs and resulting in cure (3) or improvement (5) in hypertension. Eight had bilateral aldosterone production. Four studies were inconclusive. Patients with initial unsatisfactory AVS because of bilaterally low A/F ratios had significantly (P = 0.023) more unilateral disease [10 of 18 satisfactory repeat studies (55.6%) vs. 326 of 1066 satisfactory initial studies (30.6%)] and a significantly higher (67.6 vs. 49.9%, P = 0.034) percentage of males. Conclusion: As the incidence of APAs was high in a subgroup with low A/F bilaterally on initial AVS, these patients should be offered repeat AVS. This might reflect both a greater dependence of aldosterone production on adrenocorticotrophic hormone (ACTH) in APAs and the pulsatile nature of ACTH secretion.

Hyperreninemic hypertension following presumed abdominal trauma

Background. An 18-year-old previously normotensive man was referred to a hypertension unit with blood pressure readings of 140–150/100–110 mmHg. Renal ultrasound had shown a right renal subcapsular fluid collection and an abdominal computed tomography scan had revealed a large cystic lesion surrounding the right kidney with a thick wall and irregular peripheral calcification consistent with a long-standing traumatic perinephric hematoma.Investigations. Physical examination, renal artery duplex ultrasonography, magnetic resonance imaging of the abdomen, isotopic renography with technetium-99m diethylenetriamine pentaacetic acid, and a renal venous renin ratio study.Diagnosis. Hyperreninemic hypertension as a result of presumed abdominal trauma.Management. Removal of the affected kidney.

Impact of different diagnostic criteria during adrenal vein sampling on reproducibility of subtype diagnosis in patients with primary aldosteronism

Introduction: In patients with primary aldosteronism (PA), adrenal vein sampling (AVS) is considered the only reliable technique to distinguish between unilateral and bilateral autonomous production of aldosterone, but agreement is lacking on the best criteria indicating successful cannulation and lateralisation. The objective of this study was to assess the impact of differing criteria for successful cannulation and lateralization on reproducibility of subtype diagnosis. Materials and Methods: Sixty two patients with confirmed PA underwent AVS on two separate occasions, because the first was unsatisfactory. We compared the different diagnoses of PA subtype reached using AVS data assessed by permissive (type 1), intermediate (type 2- Torino) and strict (type 3- Brisbane) criteria. Results: Although 91.1% of all (both first and second) AVS were ‘successful’ by type 1 criteria (50.8% by type 2 and 33.9% by type 3), in only 35% of patients was the diagnosis concordant between first and second AVS. Using the most permissive criteria, all combinations of discordance were observed, but of particular concern was the finding that in 7 patients lateralization actually changed from one side to the other. Type 1 criteria also led to a higher rate of diagnosis of unilateral PA (67.3% of ‘successful’ procedures) than type 2 (36.5%) or type 3 (26.2%). There was considerable disparity in the diagnosis reached using the three different criteria, with concordance in only 32.2%. Using either type 1 or 2 criteria, the minimal adrenal/peripheral vein cortisol ratio necessary to obtain the same diagnosis in the first and second AVS procedures was ≥ 2.75. Conclusions: Differing AVS cut-offs can have a profound impact on the diagnostic conclusions reached. The use of permissive cannulation success criteria can lead to significant numbers of patients being given a definitive subtype diagnosis when stricter criteria would have led to the study results being rejected or interpreted with great caution. Therefore the permissive criteria for successful cannulation and lateralisation on AVS should be avoided.