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1.
The spectrum of low-renin hypertension.
Buffolo, F, Monticone, S, Pecori, A, Pieroni, J, Losano, I, Cavaglià, G, Tetti, M, Veglio, F, Mulatero, P
Best practice & research. Clinical endocrinology & metabolism. 2020;(3):101399
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Abstract
Low-renin hypertension (LRH) is a frequent condition in patients with arterial hypertension, accounting for 30% of patients. Monogenic forms can cause LRH in a minority of cases. However, in the large majority of patients, LRH is caused by the combined effects of congenital and acquired factors, comprising dietary habits. Several genetic variants have been proposed as co-factors in the pathogenesis of LRH with normal-low serum aldosterone. Emerging evidences support the hypothesis that a large proportion of LRH with normal-high serum aldosterone is associated with subclinical primary aldosteronism (PA). The recent identification of aldosterone-producing cell clusters (APCCs) as the possible cause of subclinical PA, further supported the concept of a continuous spectrum of autonomous aldosterone secretion, from subclinical forms towards overt PA. In this review we describe the main aspects of LRH, focusing on molecular basis, clinical risk profile and patients' management.
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2.
Change in renal function associated with drug treatment in heart failure: national guidance.
Clark, AL, Kalra, PR, Petrie, MC, Mark, PB, Tomlinson, LA, Tomson, CR
Heart (British Cardiac Society). 2019;(12):904-910
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Abstract
Inhibitors of the renin-angiotensin-aldosterone (RAAS) system are cornerstones of the management of patients with heart failure with reduced left ventricular ejection fraction (HFrEF). However, RAAS inhibitors may cause decline in renal function and/or hyperkalaemia, particularly during initiation and titration, intercurrent illness and during worsening of heart failure. There is very little evidence from clinical trials to guide the management of renal dysfunction. The Renal Association and British Society for Heart Failure have collaborated to describe the interactions between heart failure, RAAS inhibitors and renal dysfunction and give clear guidance on the use of RAAS inhibitors in patients with HFrEF. During initiation and titration of RAAS inhibitors, testing renal function is mandatory; a decline in renal function of 30% or more can be acceptable. During intercurrent illness, there is no evidence that stopping RAAS inhibitor is beneficial, but if potassium rises above 6.0 mmol/L, or creatinine rises more than 30%, RAAS inhibitors should be temporarily withheld. In patients with fluid retention, high doses of diuretic are needed and a decline in renal function is not an indication to reduce diuretic dose: if the patient remains congested, more diuretics are required. If a patient is hypovolaemic, diuretics should be stopped or withheld temporarily. Towards end of life, consider stopping RAAS inhibitors. RAAS inhibition has no known prognostic benefit in heart failure with preserved ejection fraction. Efforts should be made to initiate, titrate and maintain patients with HFrEF on RAAS inhibitor treatment, whether during intercurrent illness or worsening heart failure.
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3.
Low-Renin Hypertension.
Athimulam, S, Lazik, N, Bancos, I
Endocrinology and metabolism clinics of North America. 2019;(4):701-715
Abstract
Low-renin hypertension affects 30% of hypertensive patients. Primary hyperaldosteronism presents with low renin and aldosterone excess. Low-renin, low-aldosterone hypertension represents a wide spectrum of disorders that includes essential low-renin hypertension, hereditary forms of hypertension, and hypertension secondary to endogenous or exogenous factors. This review addresses the different conditions that present with low-renin hypertension, discussing an appropriate diagnostic approach and highlighting the genetic subtypes within familial forms.
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An ectopic renin-secreting adrenal corticoadenoma in a child with malignant hypertension.
Kaslow, AM, Riquier-Brison, A, Peti-Peterdi, J, Shillingford, N, HaDuong, J, Venkatramani, R, Gayer, CP
Physiological reports. 2016;(5)
Abstract
A previously healthy 7-year-old male presented with hypertensive emergency, hypokalemia, and elevated plasma renin activity and aldosterone levels. There was no evidence of virilization or cushingoid features. MRI of the abdomen revealed a large (5 × 5 × 3 cm) peripherally enhancing, heterogeneous mass arising from the left adrenal gland. The patient was treated for a suspected pheochromocytoma. However, his blood pressure was not responsive to alpha-blockade. Blood pressure was controlled with a calcium channel blocker and an angiotensin-converting enzyme (ACE) inhibitor. A complete surgical resection of the mass was performed. Postoperatively, his blood pressure normalized and he did not require antihypertensives. On pathological examination, the tumor tissue stained negative for chromogranin and positive for renin. The final diagnosis was renin-secreting adrenal corticoadenoma, an extremely rare adrenal tumor not previously reported in a pediatric patient. Malignant hypertension due to a renin-secreting tumor may need to be distinguished from a pheochromocytoma if alpha-adrenergic blockade is ineffective.
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5.
Effect of sodium intake on renin level: Analysis of general population and meta-analysis of randomized controlled trials.
Rhee, OJ, Rhee, MY, Oh, SW, Shin, SJ, Gu, N, Nah, DY, Kim, SW, Lee, JH
International journal of cardiology. 2016;:120-6
Abstract
BACKGROUND We evaluated the association between sodium intake and plasma renin levels in the cross sectional study and meta-analysis of randomized controlled trials, whether there is a persistent elevation of plasma renin by longer-term sodium intake restriction. METHODS Plasma renin activity (PRA) and 24-h urine sodium (24HUNa) excretion were measured from individuals randomly selected from a community. Simple and multiple linear regression analyses adjusted for age, 24-h systolic blood pressure, 24-h average heart rate, fasting blood glucose and gender were performed. For meta-analysis, 74 studies published from 1975 to mid-2014 were identified in a systematic literature search using EMBASE, CINAHL, and MEDLINE. Random effects meta-analyses and a meta-regression analysis were performed. RESULTS Among the 496 participants recruited, 210 normotensive and 87 untreated hypertensive subjects were included in the analysis. There was no significant association between PRA and 24HUNa in the total population, or hypertensive and normotensive individuals. In the meta-analysis, the standard mean difference (SMD) of renin level by sodium intake reduction was 1.26 (95% CI: 1.08 to 1.44, Z=12.80, P<0.001, I(2)=87%). In the meta-regression analysis, an increase in a day of intervention was associated with a fall in SMD by -0.04 (95% CI: -0.05 to -0.02, Z=-5.27, P<0.001, I(2)=86%), indicating that longer duration of reduced sodium intake would lead to lesser SMD of renin level. CONCLUSIONS The present population based cross-sectional study and meta-analysis suggests that prolonged reduction in sodium intake is very unlikely associated with elevation of plasma renin levels.
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Management of hypertension and heart failure in patients with Addison's disease.
Inder, WJ, Meyer, C, Hunt, PJ
Clinical endocrinology. 2015;(6):789-92
Abstract
Addison's disease may be complicated by hypertension and less commonly by heart failure. We review the pathophysiology of the renin-angiotensin-aldosterone axis in Addison's disease and how this is altered in the setting of hypertension and heart failure. An essential first step in management in both conditions is optimizing glucocorticoid replacement and considering dose reduction if excessive. Following this, if a patient with Addison's disease remains hypertensive, the fludrocortisone dose should be reviewed and reduced if there are clinical and/or biochemical signs of mineralocorticoid excess. In the absence of such signs, where the renin is towards the upper end of the normal range or elevated, an angiotensin II (AII) receptor antagonist or angiotensin converting enzyme (ACE) inhibitor is the treatment of choice, and the fludrocortisone dose should remain unchanged. Dihydropyridine calcium channel blockers are clinically useful as second line agents, but diuretics should be avoided. In the setting of heart failure, there is an increase in total body sodium and water; therefore, it is appropriate to reduce and rarely consider ceasing the fludrocortisone. Loop diuretics may be used, but not aldosterone antagonists such as spironolactone or eplerenone. Standard treatment with ACE inhibitors, or as an alternative, AII receptor antagonists, are appropriate. Measurements of renin are no longer helpful in heart failure to determine the volume status but plasma levels of brain natriuretic peptide (BNP/proBNP) may help guide therapy.
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Roles of the circulating renin-angiotensin-aldosterone system in human pregnancy.
Lumbers, ER, Pringle, KG
American journal of physiology. Regulatory, integrative and comparative physiology. 2014;(2):R91-101
Abstract
This review describes the changes that occur in circulating renin-angiotensin-aldosterone system (RAAS) components in human pregnancy. These changes depend on endocrine secretions from the ovary and possibly the placenta and decidua. Not only do these hormonal secretions directly contribute to the increase in RAAS levels, they also cause physiological changes within the cardiovascular system and the kidney, which, in turn, induce reflex release of renal renin. High levels of ANG II play a critical role in maintaining circulating blood volume, blood pressure, and uteroplacental blood flow through interactions with the ANG II type I receptor and through increased production of downstream peptides acting on a changing ANG receptor phenotype. The increase in ANG II early in gestation is driven by estrogen-induced increments in angiotensinogen (AGT) levels, so there cannot be negative feedback leading to reduced ANG II production. AGT can exist in various forms in terms of redox state or complexed with other proteins as polymers; these affect the ability of renin to cleave ANG I from AGT. Thus, during pregnancy the rate of ANG I production varies not only because levels of renin change in response to homeostatic demand but also because AGT changes not only in concentration but in form. Activation of the circulating and intrarenal RAASs is essential for normal pregnancy outcome subserving the increased demand for salt and, hence, water during pregnancy. Thus, the complex integration of the secretions and actions of the circulating maternal renin-angiotensin system in pregnancy plays a key role in pregnancy outcome.
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Azilsartan, aliskiren, and combination antihypertensives utilizing renin-angiotensin-aldosterone system antagonists.
Lanier, G, Sankholkar, K, Aronow, WS
American journal of therapeutics. 2014;(5):419-35
Abstract
Health care providers managing hypertension (HTN) have a large selection of pharmacologic agents to choose from, including several different classes of drugs and many similar drugs within each class. Antagonism of the renin-angiotensin-aldosterone system has been shown to be very effective for HTN, especially in patients with cardiovascular disease, diabetes, and heart failure. Within this group, there have been 2 new agents recently introduced to the US market and approved by the Food and Drug Administration. It is important for the HTN specialist to be familiar with the merits of these 2 drugs: the angiotensin receptor blocker Edarbi (azilsartan) and the renin inhibitor Tekturna (aliskiren). Additionally, there have been several new, fixed-dose combination antihypertensives introduced to the market since 2006 that use a renin-angiotensin-aldosterone antagonist. Seven of these combine 2 drugs together in a single pill: Edarbyclor (azilsartan/chlorthalidone), Exforge (amlodipine/valsartan), Azor (olmesartan/amlodipine), Twynsta (amlodipine/telmisartan), Tekturna HCT [aliskiren/hydrochlorothiazide (HCTZ)], Valturna (aliskiren/valsartan), Tekamlo (aliskiren/amlodipine). Three triple-drug combination medications have also been introduced recently: Exforge HCT (amlodipine/valsartan/HCTZ), Tribenzor (olmesartan/amlodipine/HCTZ), and Amturnide (aliskiren/amlodipine/hydrocholorothiazide). This review will summarize the trial data and important pharmacologic merits of these 2 new renin-angiotensin-aldosterone antagonists and the advantages of initiating treatment with one of the new fixed-dose, combination drugs approved over the last 5 years.
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9.
Sequential RAAS blockade: is it worth the risk?
Persson, F, Rossing, P
Advances in chronic kidney disease. 2014;(2):159-65
Abstract
Soon after the emergence of the renin-angiotensin-aldosterone system (RAAS) blocking treatment as the cornerstone of renoprotective treatment in the prevention and treatment of diabetic and nondiabetic CKD, it was investigated if a higher degree of achievable RAAS blockade by combining more than one compound is feasible and advantageous. Regardless of the benefits from using monotherapy for diabetic kidney disease, there is still much improvement to wish for in terms of kidney prognosis in these populations. A great deal of research has gone into evaluating combinations of the RAAS blocking treatments in different populations and with different drugs and doses. Studies have mostly been short-term and use surrogate endpoints such as albuminuria. Side effects have been well known and expected in terms of increasing potassium levels and hypotension, but to an acceptable extent. With recent disappointing results from major hard endpoint trials using dual RAAS blockade the concept is now under scrutiny. In this review we will discuss the pros and cons of dual RAAS blockade, with facts and findings from smaller studies, endpoint trials, and meta-analyses.
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Renin-angiotensin system blockers may create more risk than reward for sodium-depleted cardiovascular patients with high plasma renin levels.
Sealey, JE, Alderman, MH, Furberg, CD, Laragh, JH
American journal of hypertension. 2013;(6):727-38
Abstract
BACKGROUND Four recent reports revealed differences in survival rates among treated cardiovascular patients taking renin-angiotensin system-blocking drugs. Patients with higher on-treatment plasma renin activity (PRA) levels died sooner of cardiovascular mortality than those with lower levels. We investigated whether excessive sodium depletion might have induced the higher PRA levels and contributed to the greater morbidity and mortality. METHODS Using published data, ranges of PRA, blood pressures, drug usage, and biochemical parameters were compared among various groups of cardiovascular patients. RESULTS We showed (i) that PRA levels are usually medium to low in treated cardiovascular patients, but are sometimes abnormally high, (ii) that excessive sodium depletion can induce such high PRA levels, (iii) that the higher PRA patients exhibited evidence of sodium depletion: lower blood pressures, more frequent natriuretic drug usage, lower N-terminal pro b-type natriuretic peptide (NT-proBNP), and higher blood urea nitrogen and uric acid levels, with similar usage of renin-angiotensin blocking drugs. CONCLUSIONS We hypothesize that patients with high on-treatment PRA levels die sooner of cardiovascular events because they are excessively sodium-volume depleted. Moreover, renin-angiotensin system-blocking drugs may be harmful in such patients because they can functionally interfere with the effects of reactive rises in PRA that are triggered to prevent potentially dangerous falls in blood pressure, increases in plasma potassium, and falls in glomerular filtration rate. Careful liberalization of salt intake and subtraction of natriuretic drugs, sufficient to reduce reactive hyperreninemia without inducing unacceptable increases in blood pressure, might benefit such patients and decrease risk of adverse effects from drugs that block the renin-angiotensin system.