Rise In Plasma Renin Activity Research Articles

The role of Plasma Renin Activity in prenatally diagnosed non-obstructed hydronephrosis at risk for surgery-an observational study.

Patients with asymptomatic prenatally diagnosed hydronephrosis may progress to needing surgery; no biomarker supporting the identification of these cases is currently available. The aim of the study wasto assess the role of Plasma Renin Activity (PRA) as a discriminatory factor to identify patients with asymptomatic prenatally diagnosed hydronephrosis who require close monitoring and are at-risk for surgery. The study group consists of 30 children prenatally diagnosed with asymptomatic unilateral hydronephrosis, initially managed with medical follow-up. Pyeloplasty was indicated if patients became symptomatic or if there was a significant drop in split renal function (SRF) during follow-up. An association was sought between PRA and renal parameters in post-hoc analysis. During the mean follow-up of 55.5 ± 8.2months, 13/30 (43.3%) patients developed delayed drainage and 8/30 (26.6%) underwent pyeloplasty. Mean PRA was higher at presentation in the group which later presented with a drop in differential kidney function ≥ 10%, while it was within the normal range for age in the other patients. Before pyeloplasty, progression to delayed drainage coincided with a drop in SRFand a rise in PRA. While PRA levels normalized after pyeloplasty, SRF improved but did not reach initial values. A mean rise of 68.9% in PRA preceded current indications for surgery by 27.5 ± 9.5months. A progressive increase in PRA in children with asymptomatic prenatally diagnosed hydronephrosis reflects obstructive stress in the tubulo-interstitial compartment. This stress is relieved by pyeloplasty and is reflected by a drop in PRA after surgery. PRA can, thus, serve as the discriminatory factor to identify hydronephrosis patients 'at-risk' for surgery even before the current criteria for pyeloplasty are met.

Acute and Chronic Effects of SGLT2 Inhibitor Empagliflozin on Renal Oxygenation and Blood Pressure Control in Nondiabetic Normotensive Subjects: A Randomized, Placebo-Controlled Trial.

BackgroundThe sodium/glucose cotransporter 2 inhibitor empagliflozin has cardiorenal protective properties through mechanisms beyond glucose control. In this study we assessed whether empagliflozin modifies renal oxygenation as a possible mechanism of renal protection, and determined the metabolic, renal, and hemodynamic effects of empagliflozin in nondiabetic subjects.Methods and ResultsIn this double‐blind, randomized, placebo‐controlled study, 45 healthy volunteers underwent blood and urine sampling, renal ultrasound, and blood‐oxygenation‐level–dependent magnetic resonance imaging before and 180 minutes after administration of 10 mg empagliflozin (n=30) or placebo (n=15). These examinations were repeated after 1 month of daily intake. Cortical and medullary renal oxygenation were not affected by the acute or chronic administration of empagliflozin, as determined by 148 renal blood‐oxygenation‐level–dependent magnetic resonance imaging examinations. Empagliflozin increased glucosuria (24‐hour glucosuria at 1 month: +50.1±16.3 g). The acute decrease in proximal sodium reabsorption, as determined by endogenous fractional excretion of lithium (−34.6% versus placebo), was compensated at 1 month by a rise in plasma renin activity (+28.6%) and aldosterone (+55.7%). The 24‐hour systolic and diastolic ambulatory blood pressures decreased significantly after 1 month of empagliflozin administration (−5.1 and −2.0 mm Hg, respectively). Serum uric acid levels decreased (−28.4%), hemoglobin increased (+1.7%), and erythropoietin remained the same.ConclusionsEmpagliflozin has a rapid and significant effect on tubular function, with sustained glucosuria and transient natriuresis in nondiabetic normotensive subjects. These effects favor blood pressure reduction. No acute or sustained changes were found in renal cortical or medullary tissue oxygenation. It remains to be determined whether this is the case in nondiabetic or diabetic patients with congestive heart failure or kidney disease. REGISTRATION: URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT03093103.

Plasma renin activity in patients with heart failure and reduced ejection fraction on optimal medical therapy.

Background:Renin-angiotensin-aldosterone system (RAAS) activation in heart failure with reduced ejection fraction (HFREF) is detrimental through promotion of ventricular remodeling and salt and water retention.Aims:The aims of this article are to describe RAAS activity in distinct HFREF populations and to assess its prognostic impact.Methods:Venous blood samples were prospectively obtained in 76 healthy volunteers, 72 patients hospitalized for acute decompensated HFREF, and 78 ambulatory chronic HFREF patients without clinical signs of congestion. Sequential measurements were performed in patients with acute decompensated HFREF.Results:Plasma renin activity (PRA) was significantly higher in ambulatory chronic HFREF (7.6 ng/ml/h (2.2; 18.1)) compared to patients with acute decompensated HFREF (1.5 ng/ml/h (0.8; 5.7)) or healthy volunteers (1.4 ng/ml/h (0.6; 2.3)) (all p < 0.05). PRA was significantly associated with arterial blood pressure and renin-angiotensin system blocker dose. A progressive rise in PRA (+4 ng/ml/h (0.4; 10.9); p < 0.001) was observed in acute decompensated HFREF patients after three consecutive days of decongestive treatment. Only in acute HFREF were PRA levels associated with increased cardiovascular mortality or HF readmissions (p = 0.035).Conclusion:PRA is significantly elevated in ambulatory chronic HFREF patients but is not associated with worse outcome. In contrast, in acute HFREF patients, PRA is associated with cardiovascular mortality or HF readmissions.

Insufficient evidence of benefit regarding mortality due to albumin substitution in HCC‐free cirrhotic patients undergoing large volume paracentesis

Current guidelines for clinical practice recommend the infusion of human albumin after large volume paracentesis. After inspecting the current evidence behind this recommendation, we decided to conduct a systematic review and meta-analysis in order to address the effect of albumin on mortality and morbidity in the context of large volume paracentesis. We performed a comprehensive search of large databases and abstract books of conference proceedings up to March 15th 2016 for randomized controlled trials, testing the infusion of human albumin against alternatives (vs no treatment, vs plasma expanders; vs vasoconstrictors) in HCC-free patients suffering from cirrhosis. We analyzed these trials with regard to mortality, changes in plasma renin activity (PRA), hyponatremia, renal impairment, recurrence of ascites with consequential re-admission into hospital and additional complications. We employed trial sequential analysis in order to calculate the number of patients required in controlled trials to be able to determine a statistically significant advantage of the administration of one agent over another with regard to mortality. We were able to include 21 trials totaling 1277 patients. While the administration of albumin prevents a rise in PRA as well as hyponatremia, no improvement in strong clinical endpoints such as mortality could be demonstrated. Trial sequential analysis showed that at least 1550 additional patients need to be recruited into RCTs and analyzed with regard to this question in order to detect or disprove a 25% mortality effect. There is insufficient evidence that the infusion of albumin after LVP significantly lowers mortality in HCC-free patients with advanced liver disease.

Posterior urethral valves: Persistent renin angiotensin system activation after valve ablation and role of pre-emptive therapy with angiotensin converting enzyme-inhibitors on renal recovery

Aim:To study renin angiotensin system (RAS) activity after posterior urethral valve ablation and the role of early induction of angiotensin converting enzyme-inhibitors (ACE-I) on the outcome of renal function.Materials and Methods:Thirty four children underwent valve ablation in which therapy with ACE-I was started 40.5 ± 4.1 (range 32-47 months) formed the study group. Post-ACE-I data were collected after mean duration of 18.2 ± 4.0 (12-28 months). Plasma renin activity (PRA), urinary micro albumin, glomerular filtration rate (GFR), and serum creatinine, before and after therapy were monitored.Results:Therapy with ACE-I resulted in a fall in micro albuminuria by 45.7% and 42.0% in patients without and with vesico ureteral reflux, respectively, and improvement in split renal function by 6.6% and 5.9% GFR respectively. A similar response was noted in patients without and with renal scars.Conclusion:The decline in renal function after valve ablation is accompanied by activation of RAS reflected in a gradual rise in PRA. Therapy with ACE-I stabilizes and then improves renal function, thereby, retarding the pace of renal damage.

Plasma renin activity: An early marker of progressive renal disease in posterior urethral valves

Introduction:A significant number of children with posterior urethral valves (PUV) develop chronic renal failure (CRF) due to activation of the renin angiotensin system (RAS). We investigated the role of plasma renin activity (PRA) in these cases and sought to establish a relationship between the accepted criteria of renal damage and PRA.Aims and Objectives:The aim of this study is to establish the relationship between PRA and CRF.Materials and Methods:The records of 250 patients with PUV were reviewed. Multiple linear regression analysis was used to assess correlations between PRA, grade of reflux, presence of scars and raised creatinine and decrease in glomerular filtration rates (GFR). A P < 0.5 was considered as significant.Results:A total of 58 patients were included. Their mean age was 16 years, range 5.3-24.2 years, mean follow-up period was 12.6 ± 3.6 years. At diagnosis, 22/58 (38%) patients were in CRF and 36/58 (62%) patients had normal renal function (RF). The mean PRA after treatment was higher in those who developed CRF than in those with normal RF (12.6 ± 10.2 vs. 34.6 ± 14.2 ng/ml/24 h, P = 0.02). Mean GFR at 1 year of age were 48 ± 9.8 ml/min/1.73 m2 and 86 ± 12.5 ml/min/1.73 m2 respectively (P = 0.005). PRA correlated negatively with GFR, t = –2.816,Confidence Interval:P = 0. 007. In the temporal plot over a period of 14 years, a rise in PRA preceded the fall in GFR in patients who developed CRF.Conclusions:This study shows that RAS is activated earlier in kidneys susceptible to damage. PRA could be investigated as a marker for the early detection and prevention of ongoing renal damage.

Antihypertensive Response to Thiazide Diuretic or Angiotensin Receptor Blocker in Elderly Hypertensives Is Not Influenced by Pretreatment Plasma Renin Activity

Renin profiling has been proposed as a method to guide antihypertensive drug selection. This prespecified post-hoc analysis examined the influence of baseline plasma renin activity (PRA) on blood pressure (BP) responses. A 16-week, randomized, double-blind, prompted-titration trial evaluated initial valsartan (V)/hydrochlorothiazide (HCTZ) combination therapy versus initial HCTZ or V monotherapy in individuals aged ≥ 70 years with systolic hypertension. Sitting PRA was measured at baseline, Week 4, and Week 16. Subjects were stratified into 2 groups for analysis: low renin (baseline PRA < 0.65 ng/mL/h) or normal-high renin (baseline PRA ≥ 0.65 ng/mL/h). PRA data were available in 322/384 subjects: 178 had low PRA and 144 had normal-high PRA. At Week 4, V/HCTZ was more effective than HCTZ or V at reducing mean sitting systolic BP (MSSBP), independent of baseline PRA, with reductions of -16.9, -12.6, and -9.5 mmHg, respectively, in low-renin subjects and -19.4, -11.5, and -8.6 mmHg in normal-high renin subjects. Baseline PRA was similar in responders (subjects not uptitrated at Week 4) and nonresponders (subjects uptitrated at Week 4). In responders, the reactive rise in PRA at Week 4 was related to change in MSSBP, with the greatest increases in PRA observed in the V/HCTZ group. Higher baseline PRA was associated with a greater reactive rise in PRA. Baseline PRA is not a useful guide to the BP responses of initial combination V/HCTZ in elderly individuals with systolic hypertension.

Persistent renin-angiotensin system activation after anti-reflux surgery and its management

Purpose To study renin-angiotensin system activation and the role of angiotensin-converting enzyme inhibition (ACE-I) after anti-reflux surgery. Material and Methods Thirty nine children underwent anti-reflux surgery for high grades of primary VUR. Plasma renin activity (PRA), urinary microalbumin, renal scars, split renal function (SRF), glomerular filtration rate (GFR), serum creatinine, blood pressure and episodes of breakthrough urinary tract infection were monitored in the early (5.9 ± 3.9; range 3–9 months) and late (27.1 ± 6.5; range 15–36 months) postoperative phase, before and after therapy with ACE-I (mean period 13.6 ± 2.5; range 10–24 months). Results The early postoperative improvement in renal parameters (rise in SRF and GFR by 11.2% and 7.3%, respectively, and fall in PRA by 68.8%), was not sustained subsequently (minimal improvement in SRF, 7.4%, and GFR, 0.14%, was accompanied by a rise in PRA by 92.3%). After ACE-I therapy, improvement was noted in SRF and GFR by 0.5% and 7.5%, respectively, and there was a fall in urinary microalbumin by 52.3%. Conclusions Significant down regulation of rennin-angiotensin system activation and the accompanying improvement in renal function seen early after surgery is not sustained during follow up. ACE-I aids renal recovery.

Direct renin inhibition: update on clinical investigations with aliskiren

The renin–angiotensin–aldosterone system (RAAS) plays a pivotal role in regulating blood pressure, volume, and electrolytes. The final product of RAAS cascade is angiotensin II, which exerts diverse biological activities via binding to one of three known receptor types, with different binding consequences. Despite the success with conventional strategies to limit angiotensin II production and action, these agents promote a reflex rise in plasma renin activity, which is thought to be associated with an increased incidence of cardiovascular events. Several renin inhibitors have been synthesized in order to counteract deleterious consequences of renin activity and RAAS activation; aliskiren is the first of these new non-peptide direct renin inhibitors to be approved for the treatment of hypertension. The paper reviews pharmacokinetics of aliskiren and its role in hypertension, with particular regard to those studies that compared clinical efficacy of aliskiren in comparison and in addition to other antihypertensive drug strategies.

Aliskiren Monotherapy Results in the Greatest and the Least Blood Pressure Lowering in Patients With High- and Low-Baseline PRA Levels, Respectively

Hypertensive patients with low-baseline plasma renin activity (PRA) are known to respond best to natriuretic drugs, and those with high PRA respond best to renin-angiotensin system (RAS) blockade. However, there has been recent speculation that blood pressure (BP)-lowering responses to the renin inhibitor, aliskiren, might also be blunted in some patients with medium-to-high baseline PRA. It has been suggested that treatment resistance in these patients may result from excessive reactive increases in renin secretion, such that aliskiren's blockade of PRA is overwhelmed. In order to test for evidence in support of this hypothesis, we conducted a reanalysis of original data from three published clinical trials of aliskiren. When aliskiren was administered as a monotherapy, or in combination with other blockers of the RAS, changes in PRA were closely correlated with baseline PRA. Patients with low-baseline PRA demonstrated small reductions or rises in PRA, rather than patients with medium-to-high baseline PRA. We confirmed that ambulatory BP-lowering responses to full dose aliskiren monotherapy were greatest and least among patients with high- and low-baseline PRA, respectively. However no such association was demonstrated during aliskiren combination therapy. With either monotherapy or combination therapy, no patient with a baseline PRA >0.65 ng/ml/h was observed to have a rise in both PRA and BP. We conclude, therefore, that there is only evidence for one type of resistance to aliskiren--as with all blockers of the RAS, lesser BP-lowering responses to aliskiren occur in those with the least renin to block.

Aliskiren Improves Nitric Oxide Bioavailability and Limits Atherosclerosis

Inhibition of the renin-angiotensin system (RAS), with angiotensin-converting enzyme inhibitor- (ACEI) and angiotensin receptor blocker (ARB)–based treatment approaches, has emerged as the cornerstone of contemporary cardiovascular risk reduction. These therapies offer robust reductions in cardiovascular mortality in patients postmyocardial infarction, those with systolic heart failure, and in high-risk patients with atherosclerosis. Furthermore, interruption of the RAS system has emerged as a critical modulator of normal and aberrant renal physiology, and interruption of RAS signaling is linked to improved renal structure and function.

It Is the Plasma Renin Activity Level That Counts, not Stoichiometry

HomeHypertensionVol. 52, No. 2It Is the Plasma Renin Activity Level That Counts, not Stoichiometry Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBIt Is the Plasma Renin Activity Level That Counts, not Stoichiometry Jean E. Sealey John H. Laragh Jean E. SealeyJean E. Sealey Department of Medicine, Weil Cornell Medical College, New York, NY Search for more papers by this author John H. LaraghJohn H. Laragh Department of Cardiothoracic Surgery, Weil Cornell Medical College and New York, Presbyterian Hospital, New York, NY Search for more papers by this author Originally published7 Jul 2008https://doi.org/10.1161/HYPERTENSIONAHA.108.116319Hypertension. 2008;52:e20Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 7, 2008: Previous Version 1 To the Editor:We disagree with Danser et al1 that, in patients taking the renin inhibitor aliskiren, “it is the stoichiometry that counts, not the rise in renin.” In fact, plasma renin activity (PRA) is a more explicit indicator than stoichiometry. A PRA fall during aliskiren means that renal renin secretion did not increase by much. A PRA rise means that the increase in renal renin secretion was large enough to overwhelm the aliskiren blockade of PRA. It is that simple.PRA falls during aliskiren therapy in most patients with mild-to-moderate hypertension2 (Figure). However, the magnitude of the fall differs among patients, and PRA actually increases in ≈1 in 20 patients, indicating that aliskiren can be overwhelmed by a reactive rise in renin.3 Moreover, 2 patients reported by Stanton et al2 had >20 mm Hg sustained increases in daytime systolic pressure (measured by ambulatory blood pressure monitoring), thereby indicating that blood pressure can rise during aliskiren. Download figureDownload PowerPointFigure. Medium/high renin patients had PRA >0.3 ng/mL per hour. (The Nussberger assay generates angiotensin I more slowly than the Sealey assay.) Patients with mild-to-moderate hypertension were treated for 4 weeks with 150 mg (triangles) or 300 mg (circles) of aliskiren. Vertical line=1 SD from the median value.Redrawn from Stanton et al.2A rise in blood pressure during aliskiren can alert the clinician to excessive kidney renin secretion; such a patient is likely to respond to a β-blocker, because β-blockers reduce renin secretion. However, there are 2 quite different reasons for the absence of a blood pressure fall during aliskiren. The patient may have had low renin to begin with and no renin to block, or, alternatively, renin secretion may have increased so much that it overcame the blocking action of the drug. PRA will be low in the former type of patient but not in the latter. The low-renin patient is likely to respond to a natriuretic drug,4 whereas adding a natriuretic drug instead of an antirenin drug to the hyperreactive renin patient will increase renin secretion even more to reduce the likelihood of a fall in blood pressure. Thus, knowing the PRA level is what counts, not stoichiometry.Sources of FundingThis work was supported by the May and Samuel Rudin Family Foundation, the Trust of Frederick Schwartz, and the Lawrence M. Gelb Foundation.DisclosuresJ.E.S. and J.H.L. are consultants to Diasorin Inc. J.H.L. has licensed patent 09/657.027, “Method for Evaluating and Treating Hypertension,” to Diasorin Inc.1 Danser AHJ, Charney A, Feldman DL, Nussberger J, Fisher N, Hollenberg N. The renin rise with aliskiren: it’s simple stoichiometry. Hypertension. 2008; 51: e27–e28.LinkGoogle Scholar2 Stanton A, Jensen C, Nussberger J, O'Brien E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension. 2003; 42: 1137–11433.LinkGoogle Scholar3 Sealey JE, Laragh JH. Aliskiren, the first renin inhibitor for treating hypertension: reactive renin secretion may limit its usefulness. Am J Hypertens. 2007; 20: 587–597.CrossrefMedlineGoogle Scholar4 Laragh JH. Laragh’s lessons in pathophysiology and clinical pearls for treating hypertension. Lesson XVI. How to choose the correct drug treatment for each hypertensive patient using a plasma renin based method and volume vasoconstriction analysis. Am J Hypertens. 2001; 14: 491–503.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByStanton A, Gradman A, Schmieder R, Nussberger J, Sarangapani R and Prescott M (2009) Aliskiren Monotherapy Does Not Cause Paradoxical Blood Pressure Rises, Hypertension, 55:1, (54-60), Online publication date: 1-Jan-2010. Chaudhary K, Nistala R and Whaley-Connell A (2010) Is there a future for direct renin inhibitors?, Expert Opinion on Investigational Drugs, 10.1517/13543781003781906, 19:5, (653-661), Online publication date: 1-May-2010. Nussberger J, Stanton A, Fisher N, Hollenberg N and Jan Danser A (2008) Response to It Is the Plasma Renin Activity Level That Counts, not Stoichiometry, Hypertension, 52:2, (e21-e21), Online publication date: 1-Aug-2008. August 2008Vol 52, Issue 2 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.108.116319PMID: 18606895 Originally publishedJuly 7, 2008 PDF download Advertisement SubjectsClinical StudiesDiagnostic TestingPharmacology

Captopril bei essentieller Hypertonie

The antihypertensive effect of captopril was tested on 19 patients with essential hypertension, WHO grade I or II. In 11 patients blood pressure levels returned to normal over an observation period of 12 weeks at a dose of 3 C 50-150 mg daily (group A). In eight patients with grade II hypertension the absolute blood-pressure reduction was the same, but did not reach normal levels (group B). Although additional intake of propranolol, at a dose of 3 X 40 mg daily, achieved further reduction, normal pressures were still not attained. Initial blood pressure levels were higher and plasma-renin activity lower in patients of group B than of group A. There was a definite rise in plasma-renin activity with captopril, but corresponding to the suppression of plasma-renin in severe hypertension it was less. There was a fall in plasma-aldosterone levels, corresponding to a reduced angiotensin II level as a result of inhibition of the converting enzyme. The fall in plasma-aldosterone activity was less in severe hypertension, although there was the same inhibition of converting enzyme activity in both groups. Normochromic anaemia was noted in three patients, requiring further observation and explanation. No patient developed orthostatic hypotension or reflex tachycardia.

Plasma renin activity for monitoring vesicoureteric reflux therapy: Mid-term observations

Objective To study plasma renin activity (PRA) as an early marker for monitoring treatment of vesicoureteric reflux (VUR). Patients and methods Fifty-nine children (35 males and 24 females), mean age 43.3 ± 26.5 (range 4.5–89) months, with various grades (I–V) of primary VUR were enrolled. PRA, renal scars, split renal function (SRF), glomerular filtration rate (GFR), serum creatinine, blood pressure and episodes of breakthrough urinary tract infection were monitored at regular intervals. Surgery was performed as per currently accepted criteria. PRA values were used for post-hoc analysis of results. Results Thirty-eight children (64.4%) underwent anti-reflux surgery during the mean follow up of 17.1 ± 3.1 months; 21 (35.6%) continued on non-operative follow up. Rise in PRA up to the time of surgery was seen in all patients. It normalized after surgery in 86%, and reduced but plateaued at a higher level than normal in 13.8% in the surgical group. While improvement in SRF and GFR was seen only in 2/38 (5.2%) and 12/38 (31.6%), respectively, blood pressure stabilized in 30.7% and serum creatinine showed inconsistencies. In non-operatively managed cases, improvement in SRF was seen in only one case and GFR in 14.2% of cases. However, 80.9% children showed a progressive rise in PRA throughout the period of non-operative follow up. Conclusion Current end points of non-operative management already cause irreversible renal damage by the time surgery is indicated. Our results suggest that serial measurement of plasma renin activity may help in better stratification of patients with moderate to high grade (III–V) VUR with respect to management and prognosis.

Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide

Aliskiren is a novel, orally active renin inhibitor. Its antihypertensive efficacy and safety, alone and in combination with hydrochlorothiazide (HCTZ), were investigated in an 8-week, double-blind, placebo-controlled trial in hypertensive patients. The effects of these treatments on plasma renin activity (PRA) were also assessed. A total of 2776 patients aged >or=18 years with mean sitting diastolic blood pressure (MSDBP) 95-109 mmHg were randomized to receive once-daily treatment with aliskiren (75, 150 or 300 mg), HCTZ (6.25, 12.5 or 25 mg), the combination of aliskiren and HCTZ, or placebo, in a factorial design. The primary endpoint was the change in MSDBP from baseline to week 8. PRA was assessed at these timepoints at selected study centers. Aliskiren monotherapy was superior to placebo (P < 0.001; overall Dunnett's test) in reducing MSDBP and mean sitting systolic blood pressure (MSSBP). Combination treatment was superior to both component monotherapies in reducing BP (maximum MSSBP/MSDBP reduction of 21.2/14.3 mmHg from baseline with aliskiren/HCTZ 300/25 mg), and resulted in more responders (patients with MSDBP < 90 mmHg and/or >or=10 mmHg reduction) and better control rates (patients achieving MSSBP/MSDBP < 140/90 mmHg) than either monotherapy. Aliskiren monotherapy reduced PRA by up to 65% from baseline. Although HCTZ monotherapy increased PRA by up to 72%, PRA decreased in all of the combination therapy groups. All active treatments were well tolerated. Aliskiren monotherapy demonstrated significant BP lowering, and its effect was considerably greater when combined with HCTZ. Renin inhibition with aliskiren neutralized the compensatory rise in PRA induced by HCTZ.

Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers

Aliskiren is a novel, orally active direct renin inhibitor that lowers blood pressure alone and in combination with existing antihypertensive agents. As aliskiren does not affect cytochrome P450 enzyme activities, is minimally metabolised, and is not extensively protein bound, the potential for drug interactions is predicted to be low. Four open-label studies investigated the pharmacokinetic interactions between aliskiren 300 mg and the antihypertensive drugs amlodipine 10 mg (n = 18), valsartan 320 mg (n = 18), hydrochlorothiazide 25 mg (HCTZ, n = 22) and ramipril 10 mg (n = 17) in healthy subjects. In each study, subjects received multiple once-daily doses of aliskiren and the test antihypertensive drug alone or in combination in two dosing periods separated by a drug-free washout period. Plasma concentrations of drugs were determined by liquid chromatography and mass spectrometry methods. At steady state, relatively small changes in exposure to aliskiren were observed when aliskiren was co-administered with amlodipine (AUC(tau) increased by 29%, p = 0.032), ramipril (C(max,ss) increased by 31%, p = 0.043), valsartan (AUC(tau) decreased by 26%, p = 0.002) and HCTZ (C(max,ss) decreased by 22%, p = 0.039). Co-administration with aliskiren resulted in small changes in exposure to ramipril (AUC(tau) increased by 22%, p = 0.002), valsartan (AUC(tau) decreased by 14%, p = 0.062) and HCTZ (AUC(tau) decreased by 10% and C(max,ss) by 26%, both p < 0.001). All other changes in pharmacokinetic parameters were also small, and not statistically significant. None of the observed pharmacokinetic changes was considered clinically relevant. Aliskiren inhibited plasma renin activity (PRA) and also prevented the reactive rise in PRA induced by valsartan. The most commonly reported adverse events were headache, dizziness and gastrointestinal symptoms (all mild in severity), which were similar in frequency during antihypertensive drug treatment alone and in combination with aliskiren except for an increase in dizziness during treatment with the combination of aliskiren and HCTZ. In conclusion, aliskiren shows no clinically relevant pharmacokinetic interactions and is generally well tolerated when administered in combination with amlodipine, valsartan, HCTZ or ramipril.

Effect of rofecoxib on the glomerular filtration rate, proteinuria and the renin-angiotensin-aldosterone system in elderly subjects with chronic renal impairment

Considering the increasing popularity and prescribing of specific COX-2 inhibitors, a new class of NSAIDs lacking gastrointestinal side effects, the evaluation of their effects on renal function has become very important. The aim of the study was to evaluate the effect of rofecoxib on GFR, proteinuria and the renin-angiotensin-aldosterone system (RAAS) in elderly patients with chronic renal impairment under controlled conditions of water and salt intake. There were ten patients (average age 67 years, range 53 - 80 years) with analgesic or vascular nephropathy (average GFR 54 ml/min/1.73 m2, range 30 - 79 ml/min/ 1.73 m2) given 25 mg rofecoxib daily for seven days under balanced conditions of water and sodium metabolism (salt intake 6 - 8 g/24 hours). The effect of rofecoxib on GFR measured using inulin clearance (C(in)), creatinine clearance (C(Cr)) serum cystatin C concentration (S(cystatin)), tubular creatinine secretion (using the ratio C(Cr)/C(in)), 24-hour urinary excretion of albumin (U(alb)V) and prostaglandins (U(PGE2)V and U(PGF2alpha)V), basal and stimulated plasma renin activity (PRA) and serum aldosterone concentration S(aldosterone) was evaluated before and on Day 7 during rofecoxib treatment. Rofecoxib did not significantly change C(in), C(Cr), S(cystatin), C(Cr)/C(in) and U(alb)V. However, U(PGE2)V and U(PGF2alpha)V were decreased during rofecoxib administration (p = 0.059 and p = 0.024, respectively). Rofecoxib attenuated the stimulated rise of PRA and S(aldosterone) (p = 0.019 and p = 0.008, respectively). Short-term rofecoxib administration was not associated with significant change in GFR in elderly patients with moderate chronic renal impairment under conditions of balanced salt and water metabolism despite significant attenuation of RAAS activity. Since the C(Cr)/C(in) ratio did not change in our study, we assume rofecoxib to have no influence on creatinine tubular secretion.

Cyclosporine A attenuates the natriuretic action of loop diuretics by inhibition of renal COX-2 expression

It is known that inhibition of cyclooxygenase (COX) impairs the renal actions of loop diuretics. Recently, we found that cyclosporine A (CsA) inhibits renal COX-2 expression. Therefore, we examined the interferences of CsA with the renal actions of loop diuretics. We investigated the renal effects of furosemide administration (12 mg/day subcutaneously) in male Sprague-Dawley rats receiving in addition vehicle, CsA (15 mg/kg x day), rofecoxib (10 mg/kg x day), or a combination of both. CsA, rofecoxib, and their combination lowered the furosemide-induced increase of prostaglandin E(2) (PGE(2)) and of 6-keto prostaglandin F(1 alpha) (6-keto PGF(1 alpha)) excretion by 55% and by 70%. They also lowered furosemide stimulated renal excretion of sodium and water by about 65% and 60%. Basal as well as furosemide-induced stimulation of plasma renin activity (PRA) and of renal renin mRNA was further enhanced by CsA. In contrast, rofecoxib attenuated the furosemide-induced rise of PRA and of renin mRNA, both in the absence and in the presence of CsA. In addition, the increase in plasma 6-keto PGF(1 alpha) levels by furosemide was further enhanced by CsA and was attenuated by rofecoxib. Taken together, our data suggest that CsA acts as an antinatriuretic, likely by the inhibition of COX-2-mediated renal prostanoid formation. Since the furosemide-induced stimulation of the renin system is not attenuated by CsA but by COX-2 inhibition, we speculate that extrarenal COX-2-derived prostanoids may be involved in the stimulation of the renin system by CsA and by loop diuretics.

Renin mRNA expression and renal dysfunction in tacrolimus-induced acute nephrotoxicity

Tacrolimus is a superior immunosuppressive agent and has markedly improved the short-term outcome of renal allografts. Despite the beneficial effects of maintaining immunotolerance in organ transplant recipients, it has well-characterized side effects on renal hemodynamics in the early phase. The mechanism of tacrolimus-induced acute nephrotoxicity is still unclear. The purpose of this study was to elucidate the role of renin-angiotensin system (RAS) in tacrolimus-induced acute nephrotoxicity. We examined the renal mRNA levels of renin in order to elucidate the relationship between plasma renin activity (PRA) and tacrolimus-induced renal dysfunction. Daily administration of tacrolimus (4 mg/kg/day) for 2 weeks in spontaneously hypertensive rats (SHR) significantly increased BUN and plasma creatinine (P-Cr) level, while endogenous creatinine clearance (Ccr) significantly decreased in tacrolimus treated rats. Regarding tubular function data, fractional excretion of Na (FENa) and fractional excretion of K were higher in the tacrolimus treated group. Renin mRNA levels in the renal cortex in tacrolimus treated rats significantly increased when compared to the vehicle-treated rats. Ccr level was inversely proportional to PRA, with a high correlation coeffecient. The rise in PRA significantly correlated with increase in FENa by liner regression. Therefore, the results indicate that RAS is involved in the tacrolimus-induced acute nephrotoxicity.

Effects of omapatrilat on the renin-angiotensin system in salt-sensitive hypertension

The contribution of angiotensin-(1-7) [Ang-(1-7)] to the antihypertensive actions of omapatrilat, a novel vasopeptidase inhibitor, was evaluated in 22 salt-sensitive, low renin, hypertensive subjects as a substudy of a multicenter randomized, double-blind, parallel study of 4 weeks duration. A total of 25 other subjects received lisinopril as the active control. Omapatrilat (40 mg) produced sustained control of blood pressure (BP) (as assessed by 24-h ambulatory BP measurements) that was significantly greater than that produced by 20 mg daily of lisinopril. The antihypertensive response to either drug was accompanied by similar sustained inhibition of angiotensin converting enzyme activity. Plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and Ang-(1-7) were not altered by treatment with either omapatrilat or lisinopril, even though both regimens produced a modest rise in plasma renin activity. In contrast, urinary excretion rates of Ang I and Ang-(1-7) but not Ang II increased significantly throughout the dosing period of subjects who were given omapatrilat, whereas the smaller antihypertensive response produced by lisinopril had a smaller and transient effect on increasing urinary excretion rates of Ang-(1-7). Omapatrilat, being a single molecule inhibiting neutral endopeptidase and converting enzyme simultaneously, controlled salt-sensitive hypertension by a mechanism that was associated with sustained increases in urinary Ang-(1-7) excretion. We suggest that Ang-(1-7) may be a component of the mechanisms by which omapatrilat induces an antihypertensive response in salt sensitive hypertension.