The Aldosterone/Renin Ratio as a Diagnostic Tool for the Diagnosis of Primary Hypoaldosteronism in Newborns and Infants.

BACKGROUND/AIMS: Primary hypoaldosteronism is a rare inborn disorder with life-threatening symptoms in newborns and infants due to an aldosterone synthase defect. Diagnosis is often difficult as the plasma aldosterone concentration (PAC) can remain within the normal range and thus lead to misinterpretation and delayed initiation of life-saving therapy. We aimed to test the eligibility of the PAC/plasma renin concentration (PRC) ratio as a tool for the diagnosis of primary hypoaldosteronism in newborns and infants. Meth ods: Data of 9 patients aged 15 days to 12 months at the time of diagnosis were collected. The diagnosis of primary hypoaldosteronism was based on clinical and laboratory findings over a period of 12 years in 3 different centers in Switzerland. To enable a valid comparison, the values of PAC and PRC were correlated to reference methods. RESULTS: In 6 patients, the PAC/PRC ratio could be determined and showed constantly decreased values <1 (pmol/l)/(mU/l). In 2 patients, renin was noted as plasma renin activity (PRA). PAC/PRA ratios were also clearly decreased. The diagnosis was subsequently genetically confirmed in 8 patients. CONCLUSION: A PAC/PRC ratio <1 pmol/mU and a PAC/PRA ratio <28 (pmol/l)/(ng/ml × h) are reliable tools to identify primary hypoaldosteronism in newborns and infants and help to diagnose this life-threatening disease faster. © 2015 S. Karger AG, Basel.

Active renin versus plasma renin activity to define aldosterone-to-renin ratio for primary aldosteronism

BACKGROUND: In recent years, the assessment of the plasma aldosterone-to-renin ratio (ARR) has become an established screening method for the diagnosis of primary aldosteronism. Plasma renin activity (PRA) is usually measured to define ARR although, increasingly, renin concentration alone is often measured in clinical routine. OBJECTIVE: To determine the threshold of ARR using active renin concentration to screen for primary aldosteronism. DESIGN AND PARTICIPANTS: To determine the ARR threshold based on plasma immunoreactive renin concentration (irR), we measured plasma aldosterone concentration (PAC), irR and PRA in 36 hypertensive patients, nine thereof with adrenal adenoma, and compared ARRs calculated from irR and PRA, respectively. SETTING: Single-centre, hypertension clinic in a tertiary care hospital. RESULTS: PRA ranged from 0.41-14.9 ng/ml per h and irR from 1.1-72 ng/l. There was an excellent correlation between PRA and irR (r = 0.98, P < 0.0001) and between ARRPRA and ARRirR (r = 0.96, P < 0.0001). An ARRPRA > 750 pmol/l per ng/ml per h was previously found to be highly predictive of primary aldosteronism because 90% of the corresponding patients failed to suppress PAC upon saline infusion or fludrocortisone. The corresponding threshold value for ARRirR was 150 pmol/ng in our patients. Using these cut-offs, nine subjects had both increased ARRPRA and ARRirR while, in three patients, either ARRPRA or ARRirR were increased. The nine patients with increased ARRPRA and ARRirR also had PAC > 650 pmol/l. Only these patients had adrenal adenomas. CONCLUSIONS: The ARR threshold to screen for primary aldosteronism may be based on measurement of irR. An ARRirR > 150 pmol/ng may indicate primary aldosteronism.

The aldosterone-renin ratio in screening for primary aldosteronism

Recognition that primary aldosteronism (PAL) is a common specifically treatable form of hypertension and that most patients are normokalemic has led to a marked increase in demand for aldosterone/renin ratio (ARR) testing as a means of screening for this disorder. The value of this screening test depends on an appreciation of many factors (such as diet, posture, time of day, presence of hypokalemia, medications, age, and renal function), which can affect the results, on the care with which these factors are either controlled or their effects taken into account, and on access to reliable and reproducible assays for renin and aldosterone. Even then, physiological day-to-day variability reduces the value of a single estimation, and repeated testing is necessary before a decision that PAL is highly likely (warranting further testing) or highly unlikely can be made. Provided that testing of aldosterone suppressibility is always carried out to confirm or exclude the diagnosis, and the subtype is determined by hybrid gene testing and adrenal venous sampling, wide application of the ARR can have a major beneficial clinical impact with improved therapeutic outcomes, including possible cure in those with unilateral disease.

A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22)

Familial hyperaldosteronism type II (FH-II) is caused by adrenocortical hyperplasia or aldosteronoma or both and is frequently transmitted in an autosomal dominant fashion. Unlike FH type I (FI-I-I), which results from fusion of the CYP11B1 and CYP11B2 genes, hyperaldosteronism in FH-II is not glucocorticoid remediable. A large family with FH-II was used for a genome wide search and its members were evaluated by measuring the aldosterone:renin ratio. In those with an increased ratio, FH-II was confirmed by fludrocortisone suppression testing. After excluding most of the genome, genetic linkage was identified with a maximum two point lod score of 3.26 at theta =0, between FH-II in this family and the polymorphic markers D7S511, D7S517, and GATA24F03 on chromosome 7,a region that corresponds to cytogenetic band 7p22. This is the first identified locus for FH-II; its molecular elucidation may provide further insight into the aetiology of primary aldosteronism.

Plasma renin and aldosterone measurements in low renin hypertensive states

Plasma renin concentrations are extremely low, requiring high sensitivity methods to detect low renin hypertensive states. Moreover, plasma prorenin must not cryoactivate to renin to avoid falsely high values. The enzyme kinetic plasma renin activity (PRA) test has the required sensitivity, whereas direct renin assays and PRA tests with short incubation times are usually not accurate enough. Test specificity is essential for plasma aldosterone. The Nichols Advantage aldosterone assay is fast and automated but requires great attention to quality control. Here, the impact of renin on the aldosterone:renin ratio as a screening test for primary aldosteronism is reviewed. A sensitive plasma renin test is essential for the diagnosis of low renin hypertensive states and, currently, can be consistently achieved only with the PRA radioimmunoassay.

Prevalence and diagnostic workup of primary aldosteronism: new knowledge and new approaches

No Abstract

High rate of detection of primary aldosteronism, including surgically treatable forms, after 'non-selective' screening of hypertensive patients

Background Wide testing of the aldosterone: renin ratio among hypertensive individuals has revealed primary aldosteronism to be common, with most patients normokalaemic. Some investigators, however, have reported aldosterone-producing adenoma to be rare among patients so detected. Objective To test the hypothesis that differences among reported studies in the rate of detection of aldosterone-producing adenoma (as opposed to bilateral adrenal hyperplasia) reflect differences in the procedures used for diagnosis of primary aldosteronism, and the methods used to identify aldosterone-producing adenomas. Methods In the newly established Princess Alexandra Hospital Hypertension Unit (PAHHU), we used procedures developed by Greenslopes Hospital Hypertension Unit (which reports that more than 30% of patients with primary aldosteronism have aldosterone-producing adenomas) to diagnose primary aldosteronism and determine the subtype. All patients with an increased aldosterone: renin ratio (measured after correction for hypokalaemia and while the patient was not receiving interfering medications) underwent fludrocortisone suppression testing to confirm or exclude primary aldosteronism; if they were positive, they underwent genetic testing to exclude glucocorticoid-remediable aldosteronism before adrenal venous sampling was used to differentiate lateralizing from bilateral primary aldosteronism. Results This approach allowed PAHHU to diagnose, within 2 years, 54 patients [only seven (13%) hypokalaemic] with primary aldosteronism. All tested negative for glucocorticoid-remediable aldosteronism. Aldosterone production was lateralized to one adrenal in 15 patients (31%; only six hypokalaemic) and was bilateral in 34 (69%; all normokalaemic) of 49 patients who underwent adrenal venous sampling. Among patients with lateralizing adrenal hyperplasia, computed tomography revealed an ipsilateral mass in only six and a contralateral lesion in one. Fourteen patients underwent unilateral adrenalectomy, which cured the hypertension in seven and improved it in the remainder. In patients with bilateral primary aldlosteronism, hypertension responded to spironolactone (112.5-50 mg/ day) or amiloride (2.5-10 mg/day). Conclusion When performed with careful regard to confounding factors, measurement of the aldosterone: renin ratio in all hypertensive individuals, followed by fludrocortisone suppression testing to confirm or exclude primary aldosteronism and adrenal venous sampling to determine the subtype, can result in the detection of significant numbers of patients with specifically treatable or potentially curable hypertension. (C) 2003 Lippincott Williams Wilkins.

Long-term follow-up of patients with Bartter syndrome type I and II

BACKGROUND: Little information is available on a long-term follow-up in Bartter syndrome type I and II. METHODS: Clinical presentation, treatment and long-term follow-up (5.0-21, median 11 years) were evaluated in 15 Italian patients with homozygous (n = 7) or compound heterozygous (n = 8) mutations in the SLC12A1 (n = 10) or KCNJ1 (n = 5) genes. RESULTS: Thirteen new mutations were identified. The 15 children were born pre-term with a normal for gestational age body weight. Medical treatment at the last follow-up control included supplementation with potassium in 13, non-steroidal anti-inflammatory agents in 12 and gastroprotective drugs in five patients. At last follow-up, body weight and height were within normal ranges in the patients. Glomerular filtration rate was <90 mL/min/1.73 m(2) in four patients (one of them with a pathologically increased urinary protein excretion). In three patients, abdominal ultrasound detected gallstones. The group of patients with antenatal Bartter syndrome had a lower renin ratio (P < 0.05) and a higher standard deviation score (SDS) for height (P < 0.05) than a previously studied group of patients with classical Bartter syndrome. CONCLUSIONS: Patients with Bartter syndrome type I and II tend to present a satisfactory prognosis after a median follow-up of more than 10 years. Gallstones might represent a new complication of antenatal Bartter syndrome.

Primary aldosteronism - careful investigation is essential and rewarding

Once considered rare, primary aldosteronism (PAL) is now regarded as the commonest potentially curable and specifically treatable form of hypertension. At Greenslopes Hospital Hypertension Unit (GHHU), the decision in 1991 to screen all (and not just hypokalemic or resistant) hypertensives by aldosterone/renin ratio (ARR) testing led to a 10-fold increase in detection rate of PAL and four-fold increase in removal rate of aldosterone-producing adenomas (APAs). The GHHU/Princess Alexandra Hospital Hypertension Unit PAL series stands at 977 patients and 250 APAs removed with hypertension cured in 50-60% (remainder improved). Reliable detection requires that interfering medications are withdrawn (or their effects considered) before ARR measurement, and reliable methods (such as fludrocortisone suppression testing) to confirm PAL. Adrenal venous sampling is the only dependable way to differentiate APA from bilateral adrenal hyperplasia. Genetic testing has facilitated detection of alucocorticoid-remediable, familial PAL. Identification of mutations causing the more common familial variety described by GHHU in 1991 should further aid in detection of PAL. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Hemodynamic, morphometric and autonomic patterns in hypertensive rats - renin-angiotensin system modulation

BACKGROUND: Spontaneously hypertensive rats develop left ventricular hypertrophy, increased blood pressure and blood pressure variability, which are important determinants of heart damage, like the activation of renin-angiotensin system. AIMS: To investigate the effects of the time-course of hypertension over 1) hemodynamic and autonomic patterns (blood pressure; blood pressure variability; heart rate); 2) left ventricular hypertrophy; and 3) local and systemic Renin-angiotensin system of the spontaneously hypertensive rats. METHODS: Male spontaneously hypertensive rats were randomized into two groups: young (n=13) and adult (n=12). Hemodynamic signals (blood pressure, heart rate), blood pressure variability (BPV) and spectral analysis of the autonomic components of blood pressure were analyzed. LEFT ventricular hypertrophy was measured by the ratio of LV mass to body weight (mg/g), by myocyte diameter (μm) and by relative fibrosis area (RFA, %). ACE and ACE2 activities were measured by fluorometry (UF/min), and plasma renin activity (PRA) was assessed by a radioimmunoassay (ng/mL/h). Cardiac gene expressions of Agt, Ace and Ace2 were quantified by RT-PCR (AU). RESULTS: The time-course of hypertension in spontaneously hypertensive rats increased BPV and reduced the alpha index in adult spontaneously hypertensive rats. Adult rats showed increases in left ventricular hypertrophy and in RFA. Compared to young spontaneously hypertensive rats, adult spontaneously hypertensive rats had lower cardiac ACE and ACE2 activities, and high levels of PRA. No change was observed in gene expression of Renin-angiotensin system components. CONCLUSIONS: The observed autonomic dysfunction and modulation of Renin-angiotensin system activity are contributing factors to end-organ damage in hypertension and could be interacting. Our findings suggest that the management of hypertensive disease must start before blood pressure reaches the highest stable levels and the consequent established end-organ damage is reached.

Local renin-angiotensin system regulates left ventricular hypertrophy induced by swimming training independent of circulating renin: a pharmacological study

Introduction. This study addressed the role of the local renin-angiotensin system (RAS) in the left ventriular hypertropy (LVH) induced by swimming training using pharmacological blockade. Materials and methods. Female Wistar rats treated with enalapril maleate (60 mg.kg(-1).d(-1), n = 38), losartan (20 mg.kg(-1).d(-1), n = 36) or high salt diet (1% NaCl, n = 38) were trained by two protocols (T1: 60-min swimming session, 5 days per week for 10 weeks and T2: the same T1 protocol until the 8(th) week, then 9(th) week they trained twice a day and 10(th) week they trained three times a day). Salt loading prevented activation of the systemic RAS. Haemodynamic parameters, soleus citrate synthase (SCS) activity and LVH (left ventricular/body weight ratio, mg/g) were evaluated. Results. Resting heart rate decreased in all trained groups. SCS activity increased 41% and 106% in T1 and T2 groups, respectively. LVH was 20% and 30% in T1 and T2 groups, respectively. Enalapril prevented 39% of the LVH in T2 group (p < 0.05). Losartan prevented 41% in T1 and 50% in T2 (P < 0.05) of the LVH in trained groups. Plasma renin activity (PRA) was inhibited in all salt groups and it was increased in T2 group. Conclusions. These data provide evidence that the physiological LVH induced by swimming training is regulated by local RAS independent from the systemic, because the hypertrophic response was maintained even when PRA was inhibited by chronic salt loading. However, other systems can contribute to this process.

Connexin40 regulates renin production and blood pressure.

Renin secretion is regulated by coordinated signaling between the various cells of the juxtaglomerular apparatus. The renin-secreting cells (RSC), which play a major role in the control of blood pressure, are coupled to each other and to endothelial cells by Connexin40 (Cx40)-containing channels. In this study, we show that Cx40 knockout (Cx40-/-) mice, but not their heterozygous littermates, are hypertensive due to the increase in the number of RSC, renin biosynthesis, and plasma renin. Treatment with the angiotensin II receptor AT1 antagonist candesartan or the angiotensin II-converting enzyme inhibitor ramipril reduced the blood pressure of the Cx40-/- mice to the same levels seen in wild-type (WT) mice. The elevated blood pressure of the knockout mice was not affected by clipping one renal artery (2K1C, renin-dependent model of hypertension) or after a high salt diet. Under these conditions, however, Cx40-/- mice showed an altered production and release of renin. The renin mRNA ratio between the clipped and the non-clipped kidney was lower in the knockout than in the WT 2K1C mice. This indicates that the response to a change in blood pressure was altered. The RSC of the Cx40-/- mice did not have a compensatory increase in the levels of either Cx43 or Cx37. Our data show that renin secretion is dependent on Cx40 and suggest the Cx40-/- mice may be a genetic model of renin-dependent hypertension.