Mineralocorticoid Receptor Antagonists Decrease the Rates of Positive Screening for Primary Aldosteronism

Objective: Mineralocorticoid receptor antagonists (MRAs) are effective in patients with resistant hypertension and/or primary aldosteronism (PA). Screening for PA should ideally be conducted after stopping medications that might interfere with the renin-angiotensin-aldosterone system, but this is challenging in patients with recalcitrant hypertension or hypokalemia. Herein, we aimed to evaluate the impact of MRAs on PA screening in clinical practice.Methods: We conducted a retrospective cohort study of patients with hypertension who had plasma aldosterone and renin measurements before and after MRA use in a tertiary referral center, over 19 years.Results: A total of 146 patients, 91 with PA, were included and followed for up to 18 months. Overall, both plasma renin and aldosterone increased after MRA initiation (from median, interquartile range: 0.5 [0.1, 0.8] to 1.2 [0.6, 4.8] ng/mL/hour and from 19.1 [12.9, 27.7] to 26.4 [17.1, 42.3] ng/dL, respectively; P<.0001 for both), while the aldosterone/renin ratio (ARR) decreased from 40.3 (18.5, 102.7) to 23.1 (8.6, 58.7) ng/dL per ng/mL/hour (P<.0001). Similar changes occurred irrespective of the MRA treatment duration and other antihypertensives used. Positive PA screening abrogation after MRA initiation was found in 45/94 (48%) patients. Conversely, 17% of patients had positive PA screening only after MRA treatment, mostly due to correction of hypokalemia. An initially positive screening test was more likely altered by high MRA doses and more likely persistent in patients with confirmed PA or taking beta-blockers.Conclusion: MRAs commonly reduce ARR and the proportion of positive PA screening results. When PA is suspected, screening should be repeated off MRAs.Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARR = aldosterone/renin ratio; DRC = direct renin concentration; MRA = mineralocorticoid receptor antagonist; PA = primary aldosteronism; PAC = plasma aldosterone concentration; PRA = plasma renin activity; RAAS = renin-angiotensin-aldosterone system     

Laboratory Investigation of Primary Aldosteronism

Availability and wider application of the plasma aldosterone/renin ratio (ARR) as a screening test for primary aldosteronism (PA) has led to the recognition that PA is the most common potentially curable and specifically treatable form of hypertension, possibly accounting for as many as 5–13% of patients. Aldosterone excess also has adverse cardiovascular consequences that go above and beyond hypertension development. These findings support the concept that PA plays an important role in cardiovascular disease states and should be systematically sought and specifically treated, and have led to the development of a US Endocrine Society clinical guideline for the detection, diagnosis and management of this condition. Reliable detection requires that interfering factors (including medications known to alter the ratio) are controlled before ARR measurement (or their effects taken into account), and reliable methods such as fludrocortisone suppression testing are used to confirm PA. Because computed tomography frequently misses aldosterone-producing adenomas yet demonstrates non-functioning nodules, adrenal venous sampling is the only dependable way to differentiate unilateral (surgically correctable) from bilateral (usually treated with aldosterone antagonist medications) forms of PA. For the glucocorticoid-remediable form of PA (familial hyperaldosteronism type I), genetic testing for the causative ‘hybrid’ 11beta-hydroxylase/aldosterone synthase gene has greatly facilitated detection. Laboratory assessment (including suppression testing post-operatively, and renin measurement during treatment with aldosterone antagonist medications) can assist in assessing therapeutic responses and in guiding ongoing management. Development of new, highly reliable high-throughput mass spectrometric methods for measuring aldosterone and renin should further enhance detection and reliability of diagnostic workup for PA.     

Circadian Rhythms of Plasma Renin Activity and Aldosterone: Changes Related to Age, Sex, Recumbency and Sodium Restriction. Chronobiologic Specification for Reference Values

Plasma renin activity (PRA) and aldosterone (PA) levels are characterized by a circadian rhythmicity (CR). The present study revealed that this rhythmicity is influenced by several factors including posture, sodium intake and age. Time-qualified PRA and PA reference intervals can reduce the incidence of false positives and false negatives in a diagnostic work-up. The circadian rhythmicity of PRA and PA have been quantified in relation to posture, sodium intake and age. The cosinor procedure has been applied to quantify the properties of the circadian rhythmicity under these conditions.

Chronograms and circadian parameters can be used to optimize the use of PRA and PA measurements in clinical practice. The chronobiological specification of reference values for PRA and PA is of valuable importance since the assessment of PRA and PA circadian rhythmicity has a diagnostic interest for a certain type of clinical disorder. It should be noted that several studies have described circannual variations for renin and aldosterone. The next step in the optimation of laboratory time-qualified reference values is the assessment of changes induced by the deterministic factors on a circannual domain.     

卡托普利试验过程中颈动脉斑块与醛固酮含量相关指标变化的相关性研究

目的:研究卡托普利试验过程中血浆醛固酮(PAC)相关指标的变化与颈动脉斑块的相关性。方法:选择在本院住院进行高血压病因筛查并完成了卡托普利试验,且颈动脉彩超资料完整的83例患者为研究对象。以颈动脉彩超诊断结果为分组标准,有颈动脉斑块者为斑块组(57例),无颈动脉斑块者为无斑块组(26例),分析两组患者PAC、血浆肾素活性(PRA)、PAC与PRA的比值(ARR)等指标的变化与颈动脉斑块之间的相关性。结果:颈动脉斑块检出率为68.67%。与无斑块组比较,斑块组患者的年龄更大,载脂蛋白A1(APOA1)水平更低(P均<0.05),卡托普利试验前后斑块组患者的ARR差值更低,PAC及PRA的差值更大(P均<0.05);其中,斑块组PAC及PRA的差值为正;无斑块组此二差值为负,斑块组ARR的差值为负,无斑块组该差值为正。Logistic回归分析表明,在排除了性别等因素之后,仅年龄、卡托普利试验前后PAC差值及ARR差值为颈动脉斑块形成独立的危险因素。结论:在进行高血压病因筛查的住院高血压患者中,颈动脉斑块的检出率较高,卡托普利试验前后PAC的差值及ARR的差值为颈动脉斑块形成独立的危险因素。     

Increased aldosterone/renin quotient in obese hypertensive women: a novel role for low-density lipoproteins?

Obesity, especially visceral obesity, is strongly associated with arterial hypertension. Indeed, obesity hypertension has to be considered as the most common form of essential hypertension. However, the exact nature of the relationship between obesity and increased blood pressure remains poorly understood. Involvement of renin-independent mechanisms has been suggested in adrenal stimulation of aldosterone secretion in obese patients. This investigation examined the plasma levels of renin, aldosterone, insulin, and HDL and LDL in obese hypertensive and obese normotensive women. The group of hypertensive obese women showed significantly reduced plasma levels of renin and increased aldosterone/renin quotient (ARQ) compared to obese normotensive women. Plasma aldosterone levels were not significantly different between hypertensive and normotensive obese women. In addition, plasma levels of LDL-cholesterol in the hypertensive obese group were significantly increased in comparison to the obese normotensive group. No differences were observed in HDL-cholesterol or total cholesterol/HDL-C ratios between the two groups. We therefore examined the effect of LDL on angiotensin II-stimulated aldosterone release from human adrenocortical H295R cells. Treatment of adrenocortical cells with LDL led to a sensitization towards stimulation by angiotensin II, dramatically increasing angiotensin II-induced aldosterone production, so the increased aldosterone/renin ratio observed in the hypertensive group may be due to the enhanced LDL levels in these patients and/or other adipocyte-derived mineralocorticoid-stimulating factors.     

Adrenomedullin and the renin-angiotensin-aldosterone system

Despite its positive inotropic effects and its propensity to stimulate the renin system, adrenomedullin (AM) is hypotensive as a result of dramatic reductions in peripheral resistance. Furthermore, it does not appear to increase aldosterone secretion in spite of often vigorous activation of circulating renin. Hence, we postulate that AM may act as a functional antagonist to angiotensin II both in the vasculature and the adrenal glomerulosa. In the series of studies performed in sheep and human (normal and circulatory disorders) reviewed here, we report significant hemodynamic and hormonal actions of AM. These actions include consistent reduction of arterial pressure associated with rises in cardiac output and hence a dramatic reduction in calculated total peripheral resistance (CTPR). AM also consistently attenuates the pressor effects of angiotensin II (but not norepinephrine). Furthermore, AM consistently increases plasma renin activity (PRA) and induces either a reduction in plasma aldosterone, dissociation between aldosterone/PRA ratio, or attenuation of angiotensin II-induced aldosterone secretion. Thus, these results clearly point to a role for AM in pressure and volume homeostasis acting, at least in part, by interaction with the renin-angiotensin-aldosterone system (RAAS).     

Results of an experiment in systematic prenatal screening for neural tube malformations by assay of alpha fetoproteins in dried blood samples (12,480 pregnancies)

Measurement of alpha-fetoprotein (AFP) in eluate of dried blood was carried out in 12,480 pregnant women, between the 10th and 30th weeks of amenorrhea. In 348 cases, AFP level was greater than normal (greater than 99th centile). 225 control measurements were performed (123 women dropped out of the study). In 173 cases, the AFP level returned to normal (1.4% false positives). In 52 cases, AFP title remained above the 99th centile: in 8 cases, the fetus was malformed (4 anencephalics, 1 spina bifida, 1 hydrocephalus, 1 laparoschisis, 1 exomphalos). Of the 44 remaining cases, 26 were multiple pregnancies, 5 were cases of acute fetal distress, 7 false positives normalized when a second control was made, 5 false positives up to the end of pregnancy, and 1 spina bifida (normal ultrasound scan on two different occasions). During this prenatal screening, 7 false negatives (0.56%) not detected by AFP assay should be noted: 3 anencephalics, 2 spina bifida, 1 hydrocephalus, 1 exomphalos. In all cases except one, the AFP test was carried out too early (before the 10th week) or too late (after the 30th week). The authors stress that screening must be done during the precise period between the 16th and 20th weeks of amenorrhea, and that close collaboration with a competent ultrasonographist is necessary. In 5 cases of false negatives where AFP assay and ultrasound scan had been carried out, the two methods are compared. Measurement of AFP in eluate of dried blood thus seems a reliable test which could be the first stage in a plan for systematic prenatal screening for certain serious fetal malformations with high incidence (1,2% in the Midi-Pyrenees region).     

Pharmacological properties of the converting enzyme inhibitor, enalapril maleate (MK-421)

Enalapril maleate (MK-421), an ethyl ester, is an angiotensin-converting enzyme (ACE) inhibitor from a novel series of substituted N-carboxymethyldipeptides. The parent diacid (MK-422) N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro of MK-421 inhibited hog plasma ACE with an I50 of 1.2 nM. Because deesterification occurs slowly or not at all in vitro, the in vitro I50 for enalapril was 1200 nM. However, both enalapril and MK-422 were potent inhibitors of ACE by the i.v. and oral routes in rats and dogs. In rats with experimental hypertension, enalapril was most potent in those models in which the renin-angiotensin system plays a dominant role (salt restriction, two-kidney Grollman) and in models rendered renin dependent by diuretics, although blood pressure reduction did occur in low or normal renin models such as spontaneously hypertensive rats, in which inhibition of ACE as measured by the blockade of angiotensin I pressor responses bore little temporal relationship to the later fall in blood pressure after enalapril.     

树脂灌血液灌流在顽固性高血压患者血液透析中的应用

目的：探讨树脂灌血液灌流对血液透析顽固性高血压患者血压及肾素-血管紧张素．醛固酮系统的影响。方法：选择我院82例,均分为I组和II组各41例,I组患者采用金宝8LR聚酰胺膜透析器进行常规透析,II组患者在常规透析的基础上串联树脂血液灌流,检测两组患者治疗前和治疗后3个月血清肌酐、尿素氮变化情况,和患者体内肾素活性、血管紧张素II和醛固酮变化情况,并对血压变化值进行比较。结果：两组患者治疗后3个月血肌酐、血尿素氮均明显较治疗前降低,I组患者治疗后3个月收缩压和舒张压较治疗前均无明显变化,II组治疗后3个月收缩压和舒张压均较治疗前明显降低,I组治疗后3个月肾素、血管紧张素II和醛固酮较治疗前无明显差异,II组治疗后3个月肾素、血管紧张素II和醛固酮较治疗前均明显降低。结论：血液透析联合树脂吸附灌在保证有效清除患者体内代谢物质的同时角色较好的控制患者血压。     

A new pooling strategy for high-throughput screening: the Shifted Transversal Design

Background  

In binary high-throughput screening projects where the goal is the identification of low-frequency events, beyond the obvious issue of efficiency, false positives and false negatives are a major concern. Pooling constitutes a natural solution: it reduces the number of tests, while providing critical duplication of the individual experiments, thereby correcting for experimental noise. The main difficulty consists in designing the pools in a manner that is both efficient and robust: few pools should be necessary to correct the errors and identify the positives, yet the experiment should not be too vulnerable to biological shakiness. For example, some information should still be obtained even if there are slightly more positives or errors than expected. This is known as the group testing problem, or pooling problem.     

Prevelence of Primary Aldosteronism in an Urban Hypertensive Population

Objective: To determine the prevalence of primary aldosteronism (PA) in hypertensive patients presenting to the primary care clinic at The Mount Sinai Hospital, regardless of the degree of hypertension and to identify clinical criteria that should prompt screening for PA.Methods: An aldosterone:renin ratio (ARR, cutoff ≥20, with plasma aldosterone concentration [PAC] ≥10 and suppressed renin) was used to prospectively screen 296 hypertensive patients (blood pressure [BP] ≥140/90) over the age of 18 from August 2012 through May 2013. Subjects who screened positive then underwent confirmatory oral salt load testing (OSLT).Results: Of the 296 patients, 14 screened positive for PA, an overall prevalence of 4.7%. Six of the 14 cases underwent confirmatory OSLT, upon which 2 were confirmed positive, for a prevalence of 0.7%. Overall, patients with confirmed PA were more likely to have resistant hypertension (42.9% vs. 18.1% (P =.0334)) and require more antihypertensive agents (2.8 ± 1.2 agents vs. 2.1 ± 1.1 agents, P =.0213). There was a trend toward lower potassium values in the cases.Conclusion: The prevalence of PA in our clinic is much lower than in reports from certain “at-risk” populations. PA screening is indicated in patients with resistant hypertension, regardless of serum potassium levels.Abbreviations:ARR = aldosterone:renin ratioACTH = adrenocorticotropic hormoneAVS = adrenal venous samplingBP = blood pressureMRA = mineralocorticoid receptor antagonistOSLT = oral salt load confirmatory testPA = primary aldosteronismPAC = plasma aldosterone concentrationPCP = primary care providerPRA = plasma renin activity     

The Deceptive Acid Phosphatases

Determination of the prostatic acid phosphatase is, theoretically, a specific test for carcinoma of the prostate, but the present laboratory techniques have produced too many false positives and false negatives to be dependable. There may be inhibitors or enzymes that interfere with these tests.Until more exact enzymes are discovered, the present acid phosphatases should not be depended upon as a criterion for the type of surgical operation in carcinoma of the prostate, nor, without biopsy, should they be taken as an indication of prostatic malignant disease.     

Local renin-angiotensin systems

The existence of a local cardiovascular renin-angiotensin system (RAS) is often invoked to explain the long-term beneficial effects of RAS inhibitors in heart failure and hypertension. The implicit assumption is that all components of the RAS are synthesized in situ, so that local angiotensin II formation may occur independently of the circulating RAS. Evidence for this assumption however is lacking. The angiotensin release from isolated perfused rat hearts or hindlimbs depends on the presence of renal renin. When calculating the in vivo angiotensin production at tissue sites in humans and pigs, taking into account the extensive regional angiotensin clearance by infusing radiolabeled angiotensin I or II, it was found that angiotensin production correlated closely with plasma renin activity. Moreover, in pigs the cardiac tissue levels of renin and angiotensin were directly correlated with their respective plasma levels, and both in tissue and plasma the levels were undetectably low after nephrectomy. Similarly, rat vascular renin and angiotensin decrease to low or undetectable levels within 48 h after nephrectomy. Aortic renin has a longer half life than plasma renin, suggesting that renin may be bound by the vessel wall. In support of this assumption, both renin receptors and renin-binding proteins have been described. Like ACE, renin was enriched in a purified membrane fraction prepared from cardiac tissue. Binding of renin to cardiac or vascular membranes may therefore be part of a mechanism by which renin is taken up from plasma. It appears that the concept of a local RAS needs to be reassessed. Local angiotensin formation in heart and vessel wall does occur, but depends, at least under normal circumstances, on the uptake of renal renin from the circulation. Tissues may regulate their local angiotensin concentrations by varying the number of renin receptors and/or renin-binding proteins, the ACE level, the amount of metabolizing enzymes and the angiotensin receptor density.Abbreviations RAS renin-angiotensin system - ANG angiotensin - ACE angiotensin-converting enzyme - PRA plasma renin activity     

Effect on maternal and fetal renal function and plasma renin activity of a high salt intake by the ewe

The effect on renal function of replacing maternal drinking water with a solution containing 0.17 M NaCl was studied in 9 ewes and their chronically catheterised fetuses over a period of 9 days. Maternal sodium intake increased from control values of 2.19 +/- 0.09 mmol/h to 44.3 +/- 7.4 (P less than 0.001) and 46.3 +/- 6.5 mmol/h (P less than 0.001) on the 3rd and 6th days of salt ingestion. Maternal plasma sodium levels were not affected, but the urinary sodium/potassium ratio increased from 0.15 +/- 0.07 to 2.26 +/- 0.34 (P less than 0.001) after 6 days and plasma renin activity fell from 2.87 +/- 0.76 to 1.00 +/- 0.25 ng/ml per h (P less than 0.05). The changes in maternal sodium intake had no effect on fetal plasma sodium levels nor on fetal plasma renin activity. Sodium excretion and fetal urinary sodium/potassium ratio did not change. However, 3 days after the ewes returned to drinking water fetal plasma renin activity was significantly higher than it was prior to maternal ingestion of 0.17 M NaCl. Fetal plasma renin activity was inversely related to fetal plasma sodium levels (P less than 0.01). The results show that changes in maternal sodium intake had no long term effect on fetal plasma sodium levels nor on fetal renal sodium excretion. The fall in maternal plasma renin activity in the absence of any change in the fetal renin activity, indicates that the fetal renin angiotensin system is controlled by factors other than those influencing the maternal renin angiotensin system. Since fetal urinary sodium/potassium ratios remained unchanged it would suggest that fetal sodium excretion is not influenced by maternal levels of aldosterone.     

A method with flexible and balanced control of false negatives and false positives for hit selection in RNA interference high-throughput screening assays: a statistical terminology

Zhang suggests a new method that is flexible and controls the balance between false negatives and false positives for hit selection in RNA high-throughput screening assays. The author shows that the same decision rules and balances can be expressed by familiar statistical terms such as type I error and power and hence connects the new method to known statistical tools. (Journal of Biomolecular Screening 2008:309-311).     

Recurrent Hyperkalaemia due to Selective Aldosterone Deficiency: Correction by Angiotensin Infusion

A patient with recurrent weakness and blurring of consciousness associated with hyperkalaemia due to aldosterone deficiency is reported. The plasma concentrations of renin, angiotensin II, and aldosterone were low and did not increase during sodium deprivation. Blood angiotensin I was also low while renin-substrate concentration was normal. Infusion of angiotensin produced a distinct rise in plasma aldosterone. The patient was treated successfully with fludrocortisol.The results support the concept that the renin-angiotensin system is an important regulator of aldosterone secretion and that in the syndrome of acquired selective hypoaldosteronism the primary abnormality may be a deficiency of renin. It is suggested that a selective lack of aldosterone should be considered in all cases of otherwise unexplained hyperkalaemia.     

High-throughput screening by mass spectrometry: comparison with the scintillation proximity assay with a focused-file screen of AKT1/PKB alpha

Mass spectrometry is an emerging format for label-free high-throughput screening. The main limitation of mass spectrometry is throughput, due to the requirement to purify samples prior to ionization. Here the authors compare an automated high-throughput mass spectrometry (HTMS) system (RapidFire) with the scintillation proximity assay (SPA). The cancer therapy target AKT1/PKBalpha was screened against a focused library of kinase inhibitors and IC50 values determined for all compounds that exhibit > 50% inhibition. A selection of additional compounds that exhibited 相似文献   

Polycystic ovary syndrome: Implications of measurement of plasma aldosterone, renin activity and progesterone

A positive correlation between aldosterone, inflammatory parameters, blood pressure and metabolic abnormalities in polycystic ovary syndrome (PCOS) has been reported in the early estrogenic phase. The aim of the study was to measure plasma aldosterone, plasma renin activity (PRA) and progesterone on the 21st day of the cycle, in women with PCOS and to consider the interrelationships between these hormones. Sixty-six consecutive normal BMI women with PCOS (median age 24 years, range 21-28 years) and 53 age- and body mass index-matched healthy controls were enrolled in the study. Aldosterone, aldosterone/PRA ratio (ARR) and Homeostasis Model Assessment (HOMA) index were significantly higher (p<0.0001) in PCOS women than controls. Positive correlations were found in PCOS but not in controls between (i) progesterone and aldosterone, (ii) aldosterone and PRA, (iii) PRA and progesterone. Mean blood pressures were within the normal range but significantly higher in PCOS than controls. The increase of plasma aldosterone, ARR and blood pressure in PCOS compared with controls is consistent with an increased mineralocorticoid effector mechanism in PCOS; prolonged therapy with spironolactone could counteract both the hyperandrogenism and reduce future cardiovascular risk.     

Effect of aldosterone on vascular angiotensin II receptors in the rat

The effect of aldosterone on the density and affinity of binding sites for 125I-labelled angiotensin II was investigated in a particulate fraction prepared from the rat mesenteric arteriolar arcades. The infusion of aldosterone 6.6 micrograms/h intraperitoneally via Alzet osmotic minipumps for 6 d produced an increase in the density of binding sites for 125I-labelled angiotensin II without change in affinity. After sodium depletion, mesenteric artery angiotensin II receptors were down-regulated as expected. An increase in the number of binding sites could be found when aldosterone was infused into sodium-depleted rats with no change in the elevated plasma renin activity. The intraperitoneal infusion of angiotensin II (200 ng X kg-1 X min-1 for 6 d) simultaneously with aldosterone resulted in down-regulation of vascular angiotensin II receptors, whereas after intravenous angiotensin II infusion (at 60 ng X kg-1 X min-1) the density of angiotensin II binding sites rose with aldosterone infusion. Plasma renin activity (PRA) was reduced and plasma angiotensin II increased in a dose-dependent fashion after angiotensin II infusion. An aldosterone concentration of 3 ng/mL for 18 h produced an increase in the number of angiotensin II binding sites in rat mesenteric artery smooth muscle cells in culture. We conclude that increased plasma aldosterone may result in up-regulation of vascular angiotensin II receptors independently of changes in plasma renin activity, and may in certain physiological states effectively antagonize the down-regulating action of angiotensin II.     

Captopril in renovascular hypertension: long-term use in predicting surgical outcome.

The angiotensin converting-enzyme inhibitor captopril was used as long-term preoperative treatment in a series of hypertensive patients with unilateral renal arterial disease. There were immediate and sustained falls in plasma angiotensin II and aldosterone concentrations, with converse increases in circulating renin and angiotensin I. In patients with sodium and potassium deficiency and secondary aldosterone excess before treatment captopril corrected the sodium and potassium deficits; in these cases the initial hypotensive response was profound but the later effect was less pronounced. When sodium and potassium state was initially normal it remained unchanged during captopril treatment, while the full hypotensive effect took up to three weeks to be attained. The immediate, but not long-term, falls in arterial pressure with captopril were proportional to the immediate decrements of plasma angiotensin II. Nevertheless, while the immediate blood-pressure reduction with captopril variously overestimated and underestimated the eventual surgical response, the absolute blood-pressure values during long-term captopril related well with those after operation. Pretreatment plasma renin and angiotensin II concentrations, while closely predicting the immediate captopril response, are fallible guides to surgical prognosis. In contrast, long-term treatment with converting-enzyme inhibitors may provide an accurate indication of surgical outcome.