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Longitudinal Changes in Prorenin and Renin in the Chronic Renal Insufficiency Cohort.
Cho, ME, Sweeney, C, Fino, N, Greene, T, Ramkumar, N, Huang, Y, Ricardo, AC, Shafi, T, Deo, R, Anderson, A, et al
American journal of nephrology. 2021;(2):141-151
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Abstract
INTRODUCTION Prorenin, a precursor of renin, and renin play an important role in regulation of the renin-angiotensin system. More recently, receptor-bound prorenin has been shown to activate intracellular signaling pathways that mediate fibrosis, independent of angiotensin II. Prorenin and renin may thus be of physiologic significance in CKD, but their plasma concentrations have not been well characterized in CKD. METHODS We evaluated distribution and longitudinal changes of prorenin and renin concentrations in the plasma samples collected at follow-up years 1, 2, 3, and 5 of the Chronic Renal Insufficiency Cohort (CRIC) study, an ongoing longitudinal observational study of 3,939 adults with CKD. Descriptive statistics and multivariable regression of log-transformed values were used to describe cross-sectional and longitudinal variation and associations with participant characteristics. RESULTS A total of 3,361 CRIC participants had plasma available for analysis at year 1. The mean age (±standard deviation, SD) was 59 ± 11 years, and the mean estimated glomerular filtration rate (eGFR, ± SD) was 43 ± 17 mL/min per 1.73 m2. Median (interquartile range) values of plasma prorenin and renin at study entry were 4.4 (2.1, 8.8) ng/mL and 2.0 (0.8, 5.9) ng/dL, respectively. Prorenin and renin were positively correlated (Spearman correlation 0.51, p < 0.001) with each other. Women and non-Hispanic blacks had lower prorenin and renin values at year 1. Diabetes, lower eGFR, and use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, and diuretics were associated with higher levels. Prorenin and renin decreased by a mean of 2 and 5% per year, respectively. Non-Hispanic black race and eGFR <30 mL/min/1.73 m2 at year 1 predicted a steeper decrease in prorenin and renin over time. In addition, each increase in urinary sodium excretion by 2 SDs at year 1 increased prorenin and renin levels by 4 and 5% per year, respectively. DISCUSSION/CONCLUSIONS The cross-sectional clinical factors associated with prorenin and renin values were similar. Overall, both plasma prorenin and renin concentrations decreased over the years, particularly in those with severe CKD at study entry.
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Effect of sodium-glucose cotransporter-2 inhibitors on aldosterone-to-renin ratio in diabetic patients with hypertension: a retrospective observational study.
Sawamura, T, Karashima, S, Nagase, S, Nambo, H, Shimizu, E, Higashitani, T, Aono, D, Ohbatake, A, Kometani, M, Demura, M, et al
BMC endocrine disorders. 2020;(1):177
Abstract
BACKGROUND Plasma aldosterone-to-renin ratio (ARR) is popularly used for screening primary aldosteronism (PA). Some medications, including diuretics, are known to have an effect on ARR and cause false-negative and false-positive results in PA screening. Currently, there are no studies on the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors, which are known to have diuretic effects, on ARR. We aimed to investigate the effects of SGLT2 inhibitors on ARR. METHODS We employed a retrospective design; the study was conducted from April 2016 to December 2018 and carried out in three hospitals. Forty patients with diabetes and hypertension were administered SGLT2 inhibitors. ARR was evaluated before 2 to 6 months after the administration of SGLT2 inhibitors to determine their effects on ARR. RESULTS No significant changes in the levels of ARR (90.9 ± 51.6 vs. 81.4 ± 62.9) were found. Body mass index, diastolic blood pressure, heart rate, fasting plasma glucose, and hemoglobin A1c were significantly decreased by SGLT2 inhibitors. Serum creatinine was significantly increased. CONCLUSION SGLT2 inhibitor administration yielded minimal effects on ARR and did not increase false-negative results in PA screening in patients with diabetes and hypertension more than 2 months after administration.
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Nadir Aldosterone Levels After Confirmatory Tests Are Correlated With Left Ventricular Hypertrophy in Primary Aldosteronism.
Ohno, Y, Sone, M, Inagaki, N, Kawashima, A, Takeda, Y, Yoneda, T, Kurihara, I, Itoh, H, Tsuiki, M, Ichijo, T, et al
Hypertension (Dallas, Tex. : 1979). 2020;(6):1475-1482
Abstract
Left ventricular hypertrophy (LVH) is often seen in patients with primary aldosteronism (PA), and the prevalence of LVH is reportedly higher among patients with PA than patients with essential hypertension. However, the correlation between aldosterone levels and LVH is undefined, and how aldosterone affects LVH in patients with PA remains unclear. We, therefore, retrospectively assessed a large PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) to reveal the factors associated with LVH in patients with PA without suspected autonomous cortisol secretion. In the 1186 patients with PA studied, the basal plasma aldosterone concentration, plasma renin activity, and the aldosterone-to-renin ratio did not significantly correlate with left ventricular LV mass index (LVMI) in single or multiple regression analyses. However, the plasma aldosterone concentration after the captopril challenge test or saline-infusion test, which are associated with autonomous aldosterone secretion, correlated significantly with LVMI, even after adjusting for patients' backgrounds, including age and blood pressure. In addition, hypokalemia and the unilateral subtype also correlated with LVMI. Longitudinal subanalysis of medically or surgically treated patients with PA showed significant reductions in LVMI in both the surgery (63.0±18.1 to 55.3±19.5 g/m2.7, P<0.001) and drug treatment (56.8±14.1 to 52.1±13.5 g/m2.7, P<0.001) groups. Our results suggest the autonomous aldosterone secretion level, not the basal aldosterone level itself, is relevant to LVH in patients with PA. In addition, the elevated LVMI seen in patients with PA is at least partially reversible with surgical or medical treatment.
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Relation of Plasma Renin Activity to Subclinical Peripheral and Coronary Artery Disease (from the Multiethnic Study of Atherosclerosis).
Unkart, JT, Allison, MA, Abdelmalek, JA, Jenny, NS, McClelland, RL, Budoff, M, Ix, JH, Rifkin, DE
The American journal of cardiology. 2020;(12):1794-1800
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Abstract
Experimental studies support a link between activation of the renin-angiotensin-aldosterone system and cardiovascular disease (CVD). The relationship with subclinical atherosclerosis is uncertain. Among 1,699 individuals without prevalent CVD from the Multiethnic Study of Atherosclerosis, we measured plasma renin activity (PRA) and aldosterone. Using multivariable logistic regression with restricted cubic splines, we assessed continuous log-transformed PRA and aldosterone associations with the ankle-brachial index (ABI) and coronary artery calcium (CAC) scores (Agatston) with adjustment for cardiovascular disease (CVD) risk factors, kidney function, and inflammatory biomarkers. In fully adjusted models mutually adjusting for PRA and aldosterone, higher PRA was associated with an ABI <1.0 (p overall <0.001, p nonlinear = 0.02) and CAC Agatston score >300 (p overall = 0.02, p nonlinear = 0.22), while aldosterone was not associated with either outcome. For example, compared to the 10th percentile (0.16 ng/ml/hr) of PRA, the 90th percentile (2.68 ng/ml/hr) had 3.6 times (OR 3.62; 95% CI: 2.13 to 6.13) and 1.7 times higher odds (odds ratio 1.67; 95% confidence interval: 1.13 to 2.48) of ABI <1.0 and CAC >300, respectively. These associations persisted after adjustment for levels of C-reactive protein, Interleukin-6, and Tumor Necrosis Factor-alpha. There were no significant differences in these associations by race/ethnicity or antihypertensive medication status. In conclusion, in a multiethnic cohort of community-living adults without prevalent clinical CVD, PRA was associated with greater burden of subclinical peripheral artery and coronary artery disease. These findings provide additional evidence that PRA may have deleterious effects on cardiovascular health through an atherosclerotic pathway.
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Effects of dapagliflozin on renin-angiotensin-aldosterone system under renin-angiotensin system inhibitor administration.
Isshiki, M, Sakuma, I, Hayashino, Y, Sumita, T, Hara, K, Takahashi, K, Shiojima, I, Satoh-Asahara, N, Kitazato, H, Ito, D, et al
Endocrine journal. 2020;(11):1127-1138
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Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are reported to prevent cardiovascular events by a mechanism possibly including diuresis and sodium excretion. In this respect, diuresis-induced compensatory upregulation of the renin-angiotensin-aldosterone (RAA) system should be clarified and we performed a randomized controlled trial using dapagliflozin, an SGLT2I. Hypertensive diabetic patients taking angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were randomly assigned to a dapagliflozin group (DAPA) or a control group (CTRL) with the difference in the changes in plasma renin activity (PRA) after 24 weeks of the treatment as the primary outcome. PRA, plasma aldosterone concentration (PAC), age, sex, BMI, blood pressure, pulse rate, eGFRcys, and HbA1c were not different between the groups at baseline. After 24 weeks, the changes in the PRA from the baseline of the DAPA (n = 44) and CTRL (n = 39) groups were 6.30 ± 15.55 and 1.42 ± 11.43 ng/mL/h, respectively (p = 0.11) although the power of detection was too small. However, post hoc nonparametric analyses revealed that there was a definite increase in the PRA and PAC in the DAPA group (p < 0.0001 and p = 0.00025, respectively) but not in the CTRL group. The PRA in the DAPA group after 24 weeks treatment was significantly elevated compared to the CTRL group (p = 0.013) but not for the PAC. Accordingly, it would be suggested that dapagliflozin may not induce a profound increase, if any, in PAC after 24 weeks of treatment in hypertensive type 2 diabetic patients under RAA suppression.
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Add-on aliskiren treatment can decrease blood pressure but requires attention to risks of renal impairment and hyperkalemia Chikushi Anti-Hypertension Trial-Rasilez® (CHAT-Ras).
Okamura, K, Takamiya, Y, Mori, K, Shirai, K, Urata, H
Clinical and experimental hypertension (New York, N.Y. : 1993). 2020;(6):545-552
Abstract
BACKGROUND Renin is the starting point of the renin angiotensin (RA) system cycle. Aliskiren (AL), which is a direct renin inhibitor, suppressed the entire RA cycle. In the present study, the efficacy of add-on of AL treatment in patients with essential hypertension (HT) was investigated. METHODS This study was a multi-center, open-label, prospective, observational study. Study subjects were patients with essential HT and poor blood pressure (BP) control, who had received calcium channel blocker monotherapy or angiotensin II receptor blocker monotherapy or had not received any BP lowering drugs. Following add-on of AL for 12 months, BP and additional laboratory findings were analyzed. RESULTS A total of 150 subjects were enrolled. There were 50 dropout subjects including discontinuation. Dropouts were the highest in the ARB combination therapy group at 9 subjects due to adverse events, and 3 of them were due to hyperkalemia. A significantly higher number of patients with chronic kidney disease (CKD) dropped out compared to patients without CKD (φ = 0.166, p < .05). BP before add-on of AL was 155/88 mmHg. After add-on of AL, BP was significantly improved and this lowering was sustained for 3 months (136/78 mmHg, p < .001), 6 months (136/77 mmHg, p < .001) and 12 months (134/78 mmHg, p < .001). In contrast, add-on of AL increased the potassium level and decreased the estimated glomerular filtration rate. CONCLUSION While add-on AL treatment achieved a favorable and sustained decrease of BP in this study, caution is necessary with regard to elevation of potassium levels and renal impairment.
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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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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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Plasma Renin Concentration is Associated With Hemodynamic Deficiency and Adverse Renal Outcome in Septic Shock.
Nguyen, M, Denimal, D, Dargent, A, Guinot, PG, Duvillard, L, Quenot, JP, Bouhemad, B
Shock (Augusta, Ga.). 2019;(4):e22-e30
Abstract
BACKGROUND In septic shock, both systemic vasodilatation and glomerular arteriole dilatation are responsible for the drop in glomerular filtration observed in early acute kidney injury. Angiotensin II has been shown to act on both mechanisms. Our objective was to evaluate the impact of renin angiotensin system activation, on hemodynamic deficiency and renal outcome in patient with septic shock and to assess whether urinary sodium could be a reliable test for high plasma renin concentration screening. METHODS This was a prospective and observational study. Inclusion criteria were early septic shock (first episode), dose of norepinephrine ≥ 0.25 μg/kg/min, before the start of substitutive corticosteroids. Plasma renin concentration, plasma aldosterone concentration, and urinary sodium were measured at inclusion. Renal outcome, organ deficiency, and 28-day survival were followed. RESULTS Plasma renin concentration was associated with worse hemodynamic deficiency and adverse renal outcome. Natriuresis was associated with shock severity but was not associated with renal outcome. Low natriuresis (< 20 mM) was associated with higher renin concentration. Those two variables were only weakly correlated. CONCLUSION Plasma renin concentration is associated with adverse renal outcome, probably through shock severity and insufficient glomerular efferent arterioles vasoconstriction. An association was observed between low natriuresis and high plasma renin concentration.
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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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Efficacy and Safety of Dual Blockade of the Renin-Angiotensin-Aldosterone System in Diabetic Kidney Disease: A Meta-Analysis.
Feng, Y, Huang, R, Kavanagh, J, Li, L, Zeng, X, Li, Y, Fu, P
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2019;(3):259-286
Abstract
INTRODUCTION Current guidelines recommend renin-angiotensin-aldosterone system (RAAS) inhibitors in the treatment of diabetic kidney disease (DKD). However, evidence suggests that the combined use of RAAS blockers may be associated with increased rates of adverse events. OBJECTIVES Our objective was to examine the efficacy and safety of dual blockade of the RAAS in patients with DKD. METHODS This was a systematic review and meta-analysis of randomized controlled trials (RCTs) published between January 1990 and January 2018 sourced via the PubMed, EMBASE, and Cochrane Library databases. RCTs were included if they investigated the efficacy and safety of dual blockade therapy compared with monotherapy in patients with DKD. Random effects models were used in meta-analysis to account for heterogeneities in effect sizes across the reviewed studies. Analyses were stratified by blood pressure and albuminuria. We further conducted subgroup analyses by considering various combinations of RAAS inhibitors. RESULTS Based on 42 RCTs with 14,576 patients, dual RAAS blockade therapy was associated with significant decreases in blood pressure, albuminuria, and proteinuria. However, dual therapy was not superior to monotherapy in terms of reductions in all-cause mortality, cardiovascular mortality, or progression to end-stage renal disease (ESRD). Significant increases in serum potassium and rates of hyperkalemia and hypotension were more common in patients treated with dual therapy. However, glomerular filtration rates (GFR) did not decrease significantly with dual therapy. In subgroup analysis, an angiotensin-converting enzyme inhibitor (ACEI) plus an angiotensin-receptor blocker (ARB) or a direct renin inhibitor (DRI) plus an ACEI/ARB did not significantly increase the risk of hyperkalemia, hypotension, and adverse events, and the risk of hypotension increased significantly within the normotensive subgroup but not within the hypertensive subgroup. The risk of hyperkalemia increased significantly in patients with DKD with macroalbuminuria but not in those with microalbuminuria. CONCLUSION Dual inhibition therapy is superior to monotherapy for blood pressure control and urine protein reduction, though such superiority does not translate into improvements in longer-term outcomes, such as reduced progression to ESRD, all-cause mortality, and cardiovascular mortality. An ACEI plus an ARB or a DRI plus an ACEI/ARB may be a safe and effective therapy for patients with DKD, and combination therapy may be suitable for patients with DKD and hypertension and microalbuminuria.