Changes In Plasma Renin Activity Research Articles

Renin Inhibition and the Long-Term Renal Function in Patients With Hypertensive Emergency: A Retrospective Cohort Study.

The rehospitalization rate in a hypertensive emergency is high, indicating the necessity for optimizing its long-term management. The role of the renin-angiotensin system (RAS) blockade in this disorder remains uncertain. We conducted a retrospective analysis involving 20 admitted patients who received aliskiren, a direct renin inhibitor (DRI), for the management of hypertensive emergency associated with elevated plasma renin activity (PRA). We analyzed the changes in blood pressure (BP), kidney function, and RAS activity in the subacute and chronic phases. The use of DRI was associated with a marked reduction in PRA (median, from 25.0 to 1.2 ng/ml/h) and serum aldosterone levels (from 404 to 130 pg/ml) during the index admission. BP also decreased from 226/143 to 142/80 mm Hg. A comparison of clinical characteristics according to the renal function indicated that dialysis-dependent patients had higher aldosterone levels than non-dialysis-dependent patients at admission, despite comparable BP levels. After a median follow-up of 567 days in non-dialysis-dependent patients with DRI, eGFR levels were significantly increased from 14.3 to 23.1 ml/min/1.73 m2. PRA levels were consistently suppressed at 0.8 ng/ml/h. We found a significant correlation between the degree of PRA suppression and changes in eGFR (r = -0.58), indicating that the effective blockade of RAS is associated with the preservation of eGFR in the study subjects. DRI can successfully suppress PRA in patients with high-renin hypertensive emergency in both subacute and chronic phases. An efficient RAS blockade is associated with preserved renal function in these patients.

Midodrine versus Albumin to Prevent Paracentesis Induced Circulatory Dysfunction in Acute on Chronic Liver Failure Patients in the Outpatient Clinic–a Randomized Controlled Trial

Paracentesis-induced circulatory disturbance (PICD) occurs in 12-20% of patients receiving human albumin for large-volume paracentesis, and can occur at lower than five liter paracentesis in acute-on-chronic liver failure (ACLF). Albumin infusions are associated with higher costs and more prolonged daycare admissions. The aim of the study was to determine if oral midodrine-hydrochloride can prevent PICD in these patients by increasing the mean arterial pressure (MAP). This open-labeled randomized controlled trial included ACLF patients undergoing paracentesis between 3 and 5L, who were randomized to receive either 20% human albumin or midodrine hydrochloride 7.5mg thrice daily for three days, 2h before paracentesis. MAP was recorded daily. The primary outcome was the plasma renin activity (PRA) on day six, and a 50% increase from baseline was considered PICD. 183 consecutive patients of ACLF were screened, and 50 patients were randomized to either arms. Alcohol was the most common underlying cause of cirrhosis. On day 6, PRA was non-significantly (P=0.056) higher in the midodrine group. The absolute change of PRA between the two groups was not significant (P= 0.093). Four (16%) patients in the albumin group and five (20%) in the midodrine group developed PICD. MAP increase was not different between the albumin and midodrine arms (P= 0.851). Midodrine was found to be more cost-effective. Three days of oral midodrine is as effective as a human-albumin infusion in preventing PICD in ACLF patients undergoing paracentesis lesser than that done in large volume paracentesis.

Effect of intravenous albumin infusion on plasma renin activity in children with decompensated cirrhosis

Background and Aim: Plasma renin activity(PRA) represents the activation of vasoconstrictor system in response to effective arterial hypovolemia that occurs in decompensated cirrhosis(DC). Albumin infusion is the standard of care in the context of spontaneous bacterial peritonitis(SBP), acute kidney injury(AKI), sepsis and to prevent post-paracentesis circulatory dysfunction. We did this study to assess the role of albumin infusion as a routine care in children with DC. Objective was to study the change and sustainable reduction of PRA(<2SD for age) by day 28 following albumin infusion.

Plasma Renin Activity after Diuretic Treatment in Patients with Stable Heart Failure: With Special Reference to its Association with Electrolyte Chloride

A recent study reported an intimate association between urinary chloride (Cl) and plasma renin activity (PRA) in acute heart failure (HF) status, reflecting normal functioning of the ‘tubulo-glomerular feedback’ mechanism. Whether the ‘tubuloglomerular feedback’ mechanism functions normally in stable HF status, however, is unclear. This study examined whether the ‘tubulo-glomerular feedback’ mechanism functions normally under resolution of worsening HF after decongestive therapy. Data from 26 patients with acute HF and its recovery after decongestive therapy were analyzed. Clinical tests included measurement of peripheral blood tests, serum and spot urinary electrolytes, plasma neurohormones, and fractional urinary excretions of electrolytes. In a total of 26 patients, PRA increased after acute HF treatment (from 1.64±2.0 to 5.48±6.1 ng/ mL/h, p=0.002). Changes in the serum logPRA and urinary Cl concentration from worsening to its recovery tended to be inversely correlated (R2 =0.12, p=0.085) and logPRA and the serum Cl concentration at recovery were inversely correlated (R2 =0.23, p=0.01). When divided into 2 groups (n=13 in each) according to the median PRA, the group with greater PRA changes showed a larger decrease in the urinary Cl concentration (from 110±44 to 72.8±38, p=0.03). The group with higher PRA at recovery showed a lower serum Cl concentration than the group with lower PRA at recovery (102±6.5 vs 107±4.2 mEq/L, p=0.04). In conclusion, the association between PRA and the serum/urinary Cl concentration is blunted in stable HF under-decongestive therapy, possibly due to the physiologic status under full cardiovascular medication compared with that in acute HF status.

125 Increased plasma renin activity during wake in a repetitive sleep restriction protocol

Abstract Introduction Insufficient sleep is associated with an increased risk of hypertension. It is well established that long-term BP regulation is modulated by the renin-angiotensin-aldosterone system (RAAS) and chronic kidney disease is a strong independent risk factor for development of cardiovascular disease. This study investigated the biomarkers of RAAS and renal function during repetitive exposures to controlled, experimental sleep restriction (SR). We hypothesized an upregulation of RAAS and increased markers of impaired renal function. Methods Twenty-one healthy participants (11 women, average age 31±2 years) completed the 22-day in-hospital SR protocol: permitted 4h of sleep/night from 0300-0700 for 3 nights followed by a recovery sleep, repeated 4 times. Blood samples were collected and plasma renin activity (PRA) was assessed in the morning (7:05am) and in the evening before bedtime (22:45pm) at baseline, experimental days (3rd day of each of the 4 blocks), and recovery. Urinary albumin to creatinine ratio (ACR) was measured from 24-h urinary collection at baseline, first and fourth SR blocks. Estimated glomerulus filtration rate (eGFR) was calculated based on the serum cystatin C levels at baseline and last block of SR. Results Percent change of evening PRA significantly increased during 4 blocks of SR and recovery (SR effect p=0.039), but not morning PRA (SR effect p=0.34). Specifically, evening PRA increased up to 98.4% in the first (p&amp;lt;0.01), 61.3% in the second (p=0.04) SR blocks, and 57.5% (p=0.05) in recovery. Urinary ACR showed no significant changes during first or fourth SR blocks (SR effect p=0.28). In addition, eGFR did not change in the fourth SR block compared to BL (paired t-test, p=0.27). Conclusion We did not see increased markers of impaired renal function (ACR or eGFR). Rather, short-term repetitive exposures to SR significantly increased percent change of PRA measured before bedtime, and evening PRA did not return to BL level during recovery. Our results suggested that sleep deficiency may contribute to hypertension through upregulation of RAAS during wake time. Support (if any) SRSF (CDA to Huan Yang), NIH (R01HL106782 to Dr. Janet Mullington), Harvard Catalyst, Harvard Clinical and Translational Science Center (UL1TR001102).

Changes in Plasma Renin Activity After Renal Artery Sympathetic Denervation

BackgroundThe renin-angiotensin-aldosterone system plays a key role in blood pressure (BP) regulation and is the target of several antihypertensive medications. Renal denervation (RDN) is thought to interrupt the sympathetic-mediated neurohormonal pathway as part of its mechanism of action to reduce BP. ObjectivesThe purpose of this study was to evaluate plasma renin activity (PRA) and aldosterone before and after RDN and to assess whether these baseline neuroendocrine markers predict response to RDN. MethodsAnalyses were conducted in patients with confirmed absence of antihypertensive medication. Aldosterone and PRA levels were compared at baseline and 3 months post-procedure for RDN and sham control groups. Patients in the SPYRAL HTN-OFF MED Pivotal trial were separated into 2 groups, those with baseline PRA ≥0.65 ng/ml/h (n = 110) versus <0.65 ng/ml/h (n = 116). Follow-up treatment differences between RDN and sham control groups were adjusted for baseline values using multivariable linear regression models. ResultsBaseline PRA was similar between RDN and control groups (1.0 ± 1.1 ng/ml/h vs. 1.1 ± 1.1 ng/ml/h; p = 0.37). Change in PRA at 3 months from baseline was significantly greater for RDN compared with control subjects (−0.2 ± 1.0 ng/ml/h; p = 0.019 vs. 0.1 ± 0.9 ng/ml/h; p = 0.14), p = 0.001 for RDN versus control subjects, and similar differences were seen for aldosterone: RDN compared with control subjects (−1.2 ± 6.4 ng/dl; p = 0.04 vs. 0.4 ± 5.4 ng/dl; p = 0.40), p = 0.011. Treatment differences at 3 months in 24-h and office systolic blood pressure (SBP) for RDN versus control patients were significantly greater for patients with baseline PRA ≥0.65 ng/ml/h versus <0.65 ng/ml/h, despite similar baseline BP. Differences in office SBP changes according to baseline PRA were also observed earlier at 2 weeks post-RDN. ConclusionsPlasma renin activity and aldosterone levels for RDN patients were significantly reduced at 3 months when compared with baseline as well as when compared with sham control. Higher baseline PRA levels were associated with a significantly greater reduction in office and 24-h SBP. (SPYRAL PIVOTAL - SPYRAL HTN-OFF MED Study; NCT02439749)

Effect of diuretics on plasma renin activity in primary hypertension: A systematic review and meta-analysis.

Plasma renin activity (PRA) is regarded as a marker of sodium and fluid homeostasis in patients with primary hypertension. Whether effects of diuretics on PRA differ according to class of diuretic, whether diuretics lead to a sustained increase in PRA, and whether changes in PRA relate to those in blood pressure (BP) is unknown. We performed a systematic review and meta-analysis of trials investigating the antihypertensive effects of diuretic therapy in which PRA and/or other biomarkers of fluid homeostasis were measured before and after treatment. Three databases were searched: MEDLINE, EMBASE and The Cochrane Central Register of Controlled Trials. Titles were firstly screened by title and abstract for relevancy before full-text articles were assessed for eligibility according to a predefined inclusion/exclusion criteria. A total of 1684 articles were retrieved of which 61 met the prespecified inclusion/exclusion criteria. PRA was measured in 30/61 studies. Diuretics led to a sustained increase in PRA which was similar for different classes of diuretic (standardised mean difference [95% confidence interval] 0.481 [0.362, 0.601], 0.729 [0.181, 1.28], 0.541 [0.253, 0.830] and 0.548 [0.159, 0.937] for thiazide, loop, mineralocorticoid receptor antagonists/potassium-sparing and combination diuretics respectively, Q = 0.897, P = .826), and did not relate to the average decrease in blood pressure. In antihypertensive drug trials, diuretics lead to a sustained increase in average PRA, which is similar across different classes of diuretic and unrelated to the average reduction in blood pressure.

Minor Change of Plasma Renin Activity during the Saline Infusion Test Provide an Auxiliary Diagnostic Value for Primary Aldosteronism.

Objective To clarify whether it has some hidden diagnostic values for PA, especially in the case of an inconclusive SIT result, we investigated the difference in changes of plasma renin activity (PRA) during SIT between patients with PA and non-PA. Methods We measured and compared the SIT parameters of 159 PA patients, 368 non-PA patients, and 43 inconclusive patients who were included in this study. Results The PA group showed a minor change of PRA during the SIT (ΔPRA, defined as (pre-SIT PRA–post-SIT PRA)) compared with the non-PA group (0.17 ng/ml/h vs. 1.07 ng/ml/h, P < 0.001). According to ROC analysis, ΔPRA showed a greater AUC than post-SIT PRA (0.897 vs. 0.855, P < 0.001). The cutoff value was 0.5 ng/ml/h, with 90.3% sensitivity and 78.6% specificity. When combined with ARR post-SIT, it showed 81.6% sensitivity and 97.0% specificity for PA diagnosis. Further analysis of 43 patients with an inconclusive SIT result who completed AVS found that ΔPRA was smaller in the confirmed PA group compared with the unconfirmed PA group (0.19 ng/ml/h vs. 0.29 ng/ml/h, P < 0.05); there was no significant difference in PAC post-SIT between two groups. ΔPRA ≤ 0.21 ng/ml/h provides 71.4% sensitivity, 80.0% specificity, and 87.0% PPV for their PA diagnosis. Conclusions PA patients show minor PRA change during SIT; the change of PRA during SIT provides an auxiliary diagnostic value for PA, especially in patients with an inconclusive SIT result.

Influence of sodium intake and change in sodium intake on plasma-renin in man.

BackgroundLow sodium intake stimulates the production and activity of renin. The aim is to analyse the association between a large range of sodium intake and the plasma renin activity (PRA).MethodsWe performed electronic searches for articles published between January 1st 1946 and March 18th 2020 and updated on January 21st 2021. Randomized controlled trials (RCTs) allocating participants to different sodium diets were included. Data were extracted from published reports. Meta-regression analyses of mean PRA versus mean sodium intake estimated by 24-hour urinary sodium excretion were performed. PROSPERO Registration number is CRD42020150355.Findings93 RCTs (102 interventions) were identified. In populations with usual/high sodium intake PRA was not associated with sodium intake. In populations with low sodium intake this association was mean -2·91 ng/ml/h per 100 mmol sodium (95% CI: -5·41– -0·42) in 60 studies of normotensive populations (n = 1769) and -1·91 ng/ml/h per 100 mmol sodium (-3·24 – -0·58) in 42 studies of hypertensive populations (n = 1267). The association of the change in PRA with the change in sodium intake was 1·32 ng/ml/h per 100 mmol sodium (0·47–2·18) in normotensive populations and 0·82 ng/ml/h per 100 mmol sodium (0·39–1·24) in hypertensive populations. Contrasting over-all bias assessments and potential effect modifiers had no independent impact on the sodium-PRA relationship. The variability between studies was considerable (I2 > 90%).InterpretationThe accelerating effect of sodium reduction on PRA towards a sodium intake of zero mmol/24 h probably explains the interstudy variability. Further studies are needed to test whether this stimulating effect on PRA reflects a physiological disadvantage potentially associated with increased mortalityFundingNone

Relationship between parathyroid hormone and renin–angiotensin–aldosterone system in hemodialysis patients with secondary hyperparathyroidism

Hyperparathyroidism (HPT) is associated with mortality and cardiovascular disease (CVD) in dialysis patients. However, its mechanism is still unclear. It is suspected that parathyroid hormone (PTH) is associated with the renin-angiotensin-aldosterone system (RAAS) as a possible mechanism. Thus, we examined their hormonal interaction in hemodialysis patients with secondary HPT. Seventeen hemodialysis patients with HPT were included. All patients underwent total parathyroidectomy (PTx). Serum intact PTH (iPTH), calcium and phosphate levels, plasma renin activity (PRA), and plasma aldosterone levels (ALD) were measured pre- and post-PTx. Pre-serum iPTH tended to be correlated with pre-PRA and were significantly correlated with pre-ALD (pre-PRA: r = 0.44, p = 0.07, pre-ALD: r = 0.49, p < 0.05). With the reduction in serum iPTH after PTx, PRA and ALD significantly decreased after PTx. Additionally, the change in serum iPTH tended to be correlated with the changes in PRA and ALD (PRA; r = 0.46, p = 0.05, ALD; r = 0.45, p = 0.06). Our results suggest that PTH could be interrelated with RAAS in hemodialysis patients with secondary HPT.

Associations Between Changes in Plasma Renin Activity and Aldosterone Concentrations and Changes in Kidney Function After Treatment for Primary Aldosteronism

IntroductionGreater reduction in estimated glomerular filtration rate (eGFR) after specific treatment for primary aldosteronism (PA) reflects improvement in glomerular hyperfiltration associated with PA and leads to better patient outcomes. However, little is known regarding the mechanisms underlying eGFR reduction after treatment for PA.MethodsWe analyzed data from the nationwide PA registry in Japan. Patients were assigned to adrenalectomy (n = 438) and mineralocorticoid receptor (MR) antagonist (n = 746) groups. We assessed associations between changes in blood pressure (BP), plasma renin activity (PRA) and plasma aldosterone concentrations (PAC), and eGFR before and 6 months after treatment for both groups.ResultsIn a multivariable linear regression, the adjusted β values (95% confidence interval [CI]) for change in eGFR after treatment were −2.76 (−4.29, −1.22) ml/min per 1.73 m2 for PRA (per 3.2 ng/ml per hour), and 1.97 (1.08, 2.85) ml/min per 1.73 m2 for PAC (per 236.1 pg/ml) in the adrenalectomy group; and −0.45 (−0.89, −0.01) ml/min per 1.73 m2 for PRA and −0.72 (−1.62, 0.18) ml/min per 1.73 m2 for PAC in the MR antagonist group. Change in mean arterial pressure after treatment was not significantly associated with change in eGFR in either group. Changes in PRA and PAC but not BP before and 6 months after treatment for PA were associated with greater reductions in eGFR.ConclusionPost-treatment improvements in glomerular hyperfiltration may be attributable to decreased MR activity in the kidneys, but not to reductions in systemic BP.

Effect of alpha agonists on the prevention of postparacentesis circulatory dysfunction in patients with refractory or recurrent ascites: a meta-analysis.

Postparacentesis circulatory dysfunction (PCD) is one of the commonest complications encountered in patients with refractory or recurrent ascites. Alpha agonists like clonidine and midodrine have been studied in various clinical trials for the prevention of PCD with varied results. This meta-analysis was done to evaluate the effect of alpha agonists on prevention of PCD in patients of refractory or recurrent ascites. A standard meta-analysis protocol was developed and registered in the International Prospective register of Ongoing Systematic Reviews. After performing a comprehensive literature search in MEDLINE, Cochrane, and International Clinical Trial Registry Platform, reviewers assessed eligibility and extracted data from five relevant articles. Preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines were followed in selection, analysis, and reporting of findings. Random effects model was used to estimate effect size. Quality assessment was done using the risk of bias assessment tool and meta-regression for probable variables affecting effect size. The random effect model analysis revealed a mean reduction of 2.63 ng/ml/h (95% CI: -4.46 to -0.8; P = 0.005) in plasma renin activity (PRA), mean reduction of 255.37 pg/ml (95% CI: -441.23 to -69.5; P = 0.007) in plasma aldosterone levels, and a mean increase of 0.14 mg/dl (95% CI: -0.13 to 0.41; P = 0.32) in serum creatinine levels favouring add-on alpha agonist group. In meta-regression, change in PRA (P = 0.79) and plasma aldosterone (P = 0.93) did not show a significant difference due to variation in follow-up duration across various studies. Add-on alpha agonists bring about a significant reduction in PRA and plasma aldosterone compared to standard medical treatment and thus prevents the occurrence of PCD in patients with refractory or recurrent ascites.

Abstract 109: Changes in Plasma Renin Activity After Renal Denervation in the Spyral Htn-Off Med Trial

Results from recent sham-controlled clinical trials demonstrate the efficacy of renal denervation (RDN) in blood pressure reduction, however the effects of RDN on the renin-angiotensin system are not clear. We sought to evaluate changes in plasma renin activity (PRA) and serum sodium levels after RDN in the absence of anti-hypertensive medications in the SPYRAL HTN-OFF MED trial. SPYRAL HTN-OFF MED is a randomized, sham-controlled trial to evaluate the impact of RDN in the absence of anti-hypertensive medications. Patients were enrolled with an office systolic BP (SBP) ≥150 and &lt;180 mmHg, office diastolic BP ≥90 mmHg, and a mean 24-hour SBP ≥140 and &lt;170 mmHg. Patients were randomized 1:1 to RDN with the SYMPLICITY Spyral™ catheter (N=38) or sham procedure (N=42). PRA and serum sodium levels were measured at baseline and 3 months post-procedure. Changes were expressed using medians and interquartile ranges and compared between groups using the Mann-Whitney U-test. Change in PRA from baseline to 3 months was significantly greater for the RDN group (n=23) -0.15 ng/mL/h [-0.76, -0.02] compared to the sham control group (n=33) 0.02 ng/mL/h [-0.16, 0.16]; p=0.018 ( Figure ). Comparison of 3-month changes in PRA using a Wilcoxon test stratified by 3 equal groups of baseline PRA also found a significant difference between groups (p=0.033). Changes in sodium levels were similar between groups: 0 mmol/L [-2, 2] (RDN, N=37) vs. 0 mmol/L [-1, 1] (control, N=41), p=0.920). In this sham-controlled feasibility trial, renal denervation was associated with a reduction in PRA but no difference in serum sodium levels was observed. The impact on sodium excretion will need to be assessed in future studies.

DOSE-DEPENDENT BIFURCATION ANALYSIS OF PLASMA RENIN ACTIVITY AFTER NICARDIPINE TREATMENT

Renin-angiotensin system is one of the general regulatory mechanisms of blood pressure. The activity of the system depends on the rate of renin secretion, therefore, plasma renin activity (PRA) is one of the main variables that mediates the effect of a number of factors on blood pressure. Consequently, the impact of a particular drug on blood pressure disorders can be evaluated by the PRA changes. In clinical practice, the administered therapeutic dose is of critical nature, and a number of methods are known for its calculation. In the present study, applying bifurcation analysis the range of the administered doses of the nicardipine (antihypertensive drug) are determined. The bifurcation diagrams show how the stability of the renin-angiotensin system depends on the administered dose.

DOSE-DEPENDENT BIFURCATION ANALYSIS OF PLASMA RENIN ACTIVITY AFTER NICARDIPINE TREATMENT

Renin-angiotensin system is one of the general regulatory mechanisms of blood pressure. The activity of the system depends on the rate of renin secretion, therefore, plasma renin activity (PRA) is one of the main variables that mediates the effect of a number of factors on blood pressure. Consequently, the impact of a particular drug on blood pressure disorders can be evaluated by the PRA changes. In clinical practice, the administered therapeutic dose is of critical nature, and a number of methods are known for its calculation. In the present study, applying bifurcation analysis the range of the administered doses of the nicardipine (antihypertensive drug) are determined. The bifurcation diagrams show how the stability of the renin-angiotensin system depends on the administered dose.

Plasma renin activity, response to aliskiren, and clinical outcomes in patients hospitalized for heart failure: the ASTRONAUT trial.

The direct renin inhibitor, aliskiren, is known to reduce plasma renin activity (PRA), but whether the efficacy of aliskiren varies based on an individual's baseline PRA in patients hospitalized for heart failure (HF) is presently unknown. We characterized the prognostic value of PRA and determined if this risk is modifiable with use of aliskiren. This pre-specified neurohormonal substudy of ASTRONAUT analysed all patients hospitalized for HF with ejection fraction (EF) ≤40% with available baseline PRA data (n = 1306, 80.9%). Risk associated with baseline PRA and short-term changes in PRA from baseline to 1 month was modelled with respect to 12-month clinical events. Median baseline PRA was 3.0 (interquartile range 0.6-16.4) ng/mL/h. Aliskiren significantly reduced PRA early after treatment initiation through 12-month follow-up compared with placebo (P < 0.001). The lowest baseline PRA quartile (<0.6 ng/mL/h) was independently predictive of lower all-cause mortality [adjusted hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31-0.81] and the composite of cardiovascular mortality and HF hospitalization (adjusted HR 0.57, 95% CI 0.40-0.79). Delta log-normalized PRA (from baseline to 1 month) was not predictive of either primary endpoint at 12 months (P ≥ 0.43). The prognostic value of baseline PRA and short-term changes in PRA did not vary by randomization to aliskiren or placebo (interaction P ≥ 0.13). Plasma renin activity is reduced early and durably by aliskiren, but this did not translate into improved clinical outcomes in ASTRONAUT. Baseline PRA or short-term reduction in PRA do not identify a subgroup who may preferentially benefit from direct renin inhibition. Clinical Trial Registration ClinicalTrials.gov Unique Identifier: NCT00894387.

Abstract 21227: Plasma Renin Activity, Response to Aliskiren, and Clinical Outcomes in Patients Hospitalized for Heart Failure: The ASTRONAUT Trial

Background: The direct renin inhibitor, aliskiren, is known to reduce plasma renin activity (PRA), but whether the efficacy of aliskiren varies based on an individual’s baseline PRA in patients hospitalized for HF is presently unknown. We characterized the prognostic value of PRA and determined if this risk is modifiable with use of aliskiren. Methods: This pre-specified neurohormonal substudy of ASTRONAUT analyzed all patients hospitalized for HF with EF≤ 40% with available baseline PRA data (n=1,306, 80.9%). Risk associated with baseline PRA and short-term changes in PRA from baseline to 1-month was modeled with respect to 12-month clinical events. Results: Median baseline PRA was 3.0 (interquartile range 0.6-16.4) ng/mL/h with marked regional heterogeneity (P&lt;0.001); Figure . Aliskiren significantly reduced PRA early after treatment initiation through 12-month follow-up compared with placebo (P&lt;0.001). The lowest baseline PRA quartile (&lt;0.6 ng/mL/h) was independently predictive of lower all-cause mortality (adj. HR 0.50, 95% CI 0.31-0.81) and the composite of CV mortality and HF hospitalization (adj. HR 0.57, 95% CI 0.40-0.79); Table . Delta log-normalized PRA (from baseline to 1 month) was not predictive of either primary endpoint at 12 months (P≥0.43). The prognostic value of baseline PRA and short-term changes in PRA did not vary by randomization to aliskiren or placebo (interaction P≥0.13). Conclusions: PRA is reduced early and durably by aliskiren, but this did not appear to translate into improved clinical outcomes in ASTRONAUT. Baseline PRA or short-term reduction in PRA do not identify a subgroup which may preferentially benefit from direct renin inhibition.

The influence of dietary sodium content on the pharmacokinetics and pharmacodynamics of fimasartan.

A low sodium diet enhances the hemodynamic effect of renin–angiotensin system blockers. It was suggested that the substrates of P-glycoprotein or cytochrome P450 3A4 were reduced on a high sodium diet. This study aimed to investigate the influence of high sodium diet on the pharmacokinetics and pharmacodynamics of fimasartan, which is a substrate of cytochrome P450 3A4 but not P-glycoprotein. The study design was a two-diet, two-period, two-sequence, randomized, open-label, and crossover with 1-week washout for diet. Eligible subjects were fed with either low sodium (50 mEq/day) diet or high sodium diet (300 mEq/day) for 7 days in the first hospitalization period and the other diet in the second period. On the seventh morning of each period, subjects received a single dose of fimasartan 60 mg in a fasted state. The serial plasma concentrations of fimasartan, serum aldosterone concentration (SAC), and plasma renin activity (PRA) were measured for pharmacokinetic–pharmacodynamic analysis. Sixteen subjects completed the study satisfying the compliance test for diets. Although the mean systemic exposure of fimasartan is slightly (≈10%) decreased on a high sodium diet, the difference was not statistically or clinically significant (P>0.05). The SAC and PRA after fimasartan administration were highly dependent on their baseline levels. The dietary sodium content influenced the baseline of SAC and PRA, but did not influence the ratio change of SAC and PRA after fimasartan treatment. The ratio change of SAC after fimasartan treatment was correlated to the systemic exposure of fimasartan (P<0.05), while the correlation between the ratio change of PRA after fimasartan treatment and the individual systemic exposure of fimasartan was not significant (P>0.05). In conclusion, the pharmacokinetics of fimasartan and ratio changes of SAC and PRA after fimasartan treatment were not significantly influenced by dietary sodium content.

Abstract 17081: Long-term Administration of Eicosapentaenoic Acid Ameliorates Vascular Endothelial Dysfunction Through the Renin-angiotensin-aldosterone System Inhibition Resulting in the Improvement of Muscle Oxygen Metabolism in Patients With Lifestyle Related Disease

Background: Elevated activity of renin-angiotensin-aldosterone system (RAAS) is known to induce vascular endothelial dysfunction in patients with lifestyle related disease such as diabetes mellitus (DM), hypertension (HT) and dyslipidemia (DL). Because the vascular endothelial dysfunction disturbs an appropriate blood flow to skeletal muscles, it is considered that the oxygen metabolism is impaired in them. Although eicosapentaenoic acid (EPA) has been reported to inhibit the RAAS, it is unclear whether EPA ameliorates vascular endothelial dysfunction via the RAAS inhibition resulting in the improvement of muscle oxygen metabolism. This study investigated the effects of EPA on vascular endothelial function and muscle oxygen metabolism during exercise in patients with lifestyle related disease. Methods: Ninety-two patients (68±8 years, 50 males) were divided into two groups based on the EPA administration in crossover method, after their DM, HT and/or DL were optimally treated. When patients took 1,800 mg of EPA daily for 8 months or not, they were in the EPA(+) group or in the EPA(-) group. In the end of each treatment period, cardiopulmonary exercise test was performed to measure oxygen uptake (VO 2 ) at anaerobic threshold (VO 2 AT ), peak VO 2 and the time from the start of the test to the AT (Time AT ) and endpoint (Time EP ). We measured serum EPA, plasma renin activity (PRA), aldosterone (ALD), adrenalin (ADRN) and noradrenalin (NORA), and reactive hyperemia index (RHI). We used the changes in PRA, ALD, ADRN and NORA before and after a cycle ergometer exercise test (ΔPRA, ΔALD, ΔADRN and ΔNORA) as neurohumoral factors, RHI as a parameter of vascular endothelial function and Time EP as an exercise capacity. Results: There were no significant differences in ΔPRA, ΔALD, ΔNORA, peak VO 2 and Time EP between the two groups. The PRA, ALD and ΔADRN were significantly lower in the EPA(+) group than in the EPA(-) group (P&lt;0.05, respectively). The RHI, VO 2 AT and Time AT were significantly higher in the EPA(+) group than in the EPA(-) group (P&lt;0.05, respectively). Conclusion: Long-term administration of EPA ameliorated vascular endothelial dysfunction via the RAAS inhibition resulting in the improvement of muscle oxygen metabolism in lifestyle related disease patients.

Increased Urine Transforming Growth Factor β1 (TGF-β1) and Serum Uric Acid Are Associated With an Early Decline of Glomerular Filtration Rate in Kidney Transplant Recipients

BackgroundThe renin-angiotensin system (RAS) and transforming growth factor β1 (TGF-β1) may play a role in the pathogenesis of fibrosis in kidney allografts. Experimental hyperuricemia shows activation of intrarenal RAS. However, the association between uric acid (UA), RAS, and TGF-β1 in allograft recipients has not been demonstrated. Therefore we investigated the association between serum UA levels, RAS, and TGF-β1 in kidney transplant recipients during the 1st year after transplantation. MethodsSixty-two transplant recipients were included in the study. Serum UA level, plasma renin activity (PRA), and urine TGF-β1 concentration were studied at 3, 6, and 12 months after transplantation. Statistical correlation was demonstrated with the use of Spearman rank correlation coefficient. Receiver operating characteristic curve analysis and area under the curve were performed to assess the diagnostic performance to discriminate between estimated glomerular filtration rate (eGFR) <60 and ≥60 mL/min/1.73 m2. ResultsFor all 62 patients, urine TGF-β1 and serum UA had a tendency to increase during the 1-year follow-up period, despite no statistically significant change in eGFR. We found that increased urine TGF-β1 was correlated with rising serum UA levels and a decrease of the eGFR (r = 0.27 [P = .01]; r = −0.38 [P = .0003]). In contrast, there was no significant change in PRA and it was not correlated with eGFR or TGF-β1 (r = −0.01; P = .93). ConclusionsIncreased urine TGF-β1 and serum UA level during the 1st year after transplantation correlated with a decline in eGFR. The evaluation of these parameters in the early post-transplantation period may identify patients at risk of allograft dysfunction.