Long-term outcomes of add-on direct renin inhibition in igA nephropathy: a propensity score-matched cohort study.

INTRODUCTION: The long-term clinical outcomes in biopsy proven IgAN patients treated with aliskiren on top of a maximally tolerated dose of ACEi/ARB remain unknown. METHODS: Patients with IgAN treated with a direct renin inhibitor and ACEi/ARB for at least 6 months were compared with a 1:1 propensityscore-matched cohort (including MEST-C score and the 12-months pre-exposure slope of eGFR matching) who received ACEi/ARB without aliskiren exposure to compute the hazard ratio of reaching the primary endpoint of a composite of 40% reduction in eGFR, initiation of KRT and all-cause mortality. Secondary outcome measures included changes in mean UPCR, blood pressure, eGFR, incidence of hyperkalemia and other adverse events during follow-up. RESULTS: After a median follow-up of 2.5 years, 8/36 (22.2%) aliskiren-treated patients and 6/36 (16.7%) control patients reached the primary composite outcome (HR = 1.60; 95% CI 0.52-4.88; P = 0.412). Aliskiren treatment increased the risk of ≥ 40% eGFR decline (HR = 1.60; 95% CI 0.52-4.88; P = 0.412), and hyperkalemia (HR = 8.60; 95% CI 0.99-73.64; P = 0.050). At 10.8 years, renal composite outcome was reached in 69.4% vs 58.3% (HR = 2.16; 95% CI 1.18-3.98; P = 0.013) of patients in the aliskiren and control groups, respectively. The mean UPCR reduction between treatment and control was not statistically different (52.7% vs 42.5%; 95% CI 0.63-2.35; P = 0.556). The mean intergroup difference in eGFR decline over 60 months was 7.75 ± 3.95 ml/min/1.73 m2 greater in the aliskiren group (12.83 vs 5.08; 95% CI - 0.17 to 15.66; P = 0.055). CONCLUSION: Among patients with IgAN, add-on aliskiren was associated with less favorable long-term kidney outcomes despite an initial anti-proteinuric effect.

Efficacy of Direct Renin Inhibitors in Slowing Down the Progression of Diabetic Kidney Disease: A Meta-Analysis.

Albuminuria is a risk factor for chronic kidney disease and cardiovascular events in diabetic people. The pathogenic processes in these circumstances have been documented to be significantly influenced by enhanced renin-angiotensin system activity. The current meta-analysis was carried out to assess the efficacy of direct renin inhibitors in preventing the progression of diabetic kidney disease. This meta-analysis was conducted as per the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched the relevant medical literature through PubMed, Cochrane library and EMBASE. The primary efficacy outcome was a percentage change in urine albumin-creatinine ratio (UACR) (in mg/g) level. Other primary efficacy outcomes included remission from microalbuminuria to normal albuminuria and progression from microalbuminuria to macroalbuminuria. Four randomized control studies were identified and included in the current meta-analysis involving 9,609 participants. The use of direct renin inhibitors was superior in reducing mean UACR compared to angiotensin receptor blockers and angiotensin-converting enzyme inhibitors. The pooled mean difference in UACR between direct renin inhibitors and the control group was 9.42% (95% CI: -15.70 to -3.15: p-value=0.003). The odds of progression from microalbuminuria to normal albuminuria are 1.26 times higher in patients receiving direct renin inhibitors compared to patients in the control group (OR: 1.26, 95% CI: 1.08-1.46, p-value=0.002). The odds of remission from microalbuminuria to macroalbuminuria were 20% lower in patients receiving direct renin inhibitors compared to patients in the control group (OR: 0.80, 95% CI: 0.69-0.93, p-value=0.003). The use of aliskiren is associated with a significant reduction in UACR, increased remission from microalbuminuria to normal albuminuria and decreased progression from microalbuminuria to macroalbuminuria.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SPH3127: A Phase I, Randomized, Double-Blind, Placebo-Controlled Trial.

PURPOSE: To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of single- and multiple-dose SPH3127 in healthy individuals. METHODS: This was a randomized, double-blind, placebo-controlled, Phase I dose-escalation study. FINDINGS: SPH3127 exposure, expressed as Cmax, AUC0-t, and AUC0-∞, was proportionally increased with dose for a range of 25-800 mg (single ascending dose [SAD]) and 100-400 mg daily (multiple ascending doses [MADs]). In an SAD, the Cmax values with 25, 50, 100, 200, 400, and 800 mg of SPH3127 were 90.67, 344.50, 523.50, 1239.50, 2445.00, and 5753.33 ng/mL, respectively. The corresponding AUC0-t values were 294.48, 843.62, 1109.33, 2858.56, 6697.50, and 13057.83 h × ng/mL. In MADs, after the first dose of SPH3127, the Cmax values with 100, 200, and 400 mg of SPH3127 were 421.50, 969.00, and 2468.33 ng/mL, respectively. The corresponding AUC0-t values were 1279.28, 2275.77, and 5934.26 h × ng/mL. At steady state, the Cmax values with 100, 200, and 400 mg of SPH3127 were 514.67, 1419.17, and 2513.33 ng/mL, respectively. The corresponding AUC0-24 values were 1638.14, 3096.20, and 7577.70 h × ng/mL. The median Tmax range from 0.33 to 1.0 h and the median t1/2 from 3 to 4 h. In an SAD, when the dose was >100 mg, plasma renin activity inhibition of up to 90% lasted up to 24 h. In MADs, renin activity was continuously inhibited by up to 90% in each group for 24 h after the last administration. Treatment-emergent adverse events (AEs) were reported in 29.2% of individuals receiving the SAD and 33.3% of those receiving MADs. Only mild adverse events occurred. IMPLICATIONS: SPH3127 was well tolerated and had robust and sustained suppression of plasma renin activity. CLINICALTRIALS. GOV IDENTIFIERS: NCT03128138 (SAD study) and NCT03255993 (MAD study).

Functional and molecular evaluation of using aliskiren during acute and chronic partial ureteral obstruction in rat solitary kidney.

AIMS: To study the effect of direct renin inhibitor (aliskiren) on the renal function during acute and chronic partial ureteral obstruction (PUO) in rat solitary kidney. MAIN METHODS: Sixty male Sprague-Dawley rats were randomly allocated into three groups (20 rats each); sham, PUO and aliskiren groups. Right nephrectomy was performed in all groups. Rats in PUO and aliskiren groups were subjected to left PUO and received no treatment and aliskiren (10 mg/kg, orally, once per day till sacrification), respectively. Blood samples were then collected for biochemical measurements. Ten rats from each group were sacrificed after two weeks, while the remaining rats were sacrificed after four weeks. Left kidneys were harvested for histopathological examination, BCL-2, interleukin (IL)-6, transforming growth factor (TGF)-ß1, collagen I and fibronectin relative gene expression and assessment of glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) activity. KEY FINDINGS: After two and four weeks of PUO, aliskiren significantly recompensed the rise of serum creatinine (Scr) and blood urea nitrogen (BUN). Aliskiren also revealed significantly better histopathological results regarding cortical and medullary necrosis, regeneration and inflammatory cell infiltration. Aliskiren group showed statistically significant up-regulation of BCL-2 and down-regulation of IL-6, TGF-ß1, collagen I and fibronectin relative gene expression. Aliskiren significantly increased GSH and SOD activity and reduced MDA and NO activity. Moreover, aliskiren administration for four weeks after PUO significantly yielded more renoprotective effect compared to its administration for two weeks. SIGNIFICANCE: Aliskiren ameliorates the deterioration of the renal function during acute and chronic PUO in a solitary kidney.

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).

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.

Evaluation of preclinical safety profile of SPH3127, a direct renin inhibitor, after 28-day repeated oral administration in Sprague-Dawley rats and cynomolgus monkeys.

SPH3127, a newly developed oral nonpeptide direct renin inhibitor with good tolerance and favorable ADME (absorption distribution metabolism excretion) properties in preclinical species, is now being evaluated in phase Ι clinical trial. In this work, the subchronic toxicity of SPH3127 in Sprague-Dawley rats and cynomolgus monkeys has been characterized. Rats and monkeys received SPH3127 orally (30, 300, 900 and 20, 100, 450 mg/kg/day, respectively) on a consecutive daily dosing schedule for 28 days followed by a 28-days recovery period for one third of the animals. The adverse effects of SPH3127 on rats and monkeys mainly included kidney and cardiovascular toxicity, which were consistent with pharmacologic perturbations of physiologic processes associated with the intended molecular targets for this class of renin signaling inhibitors. Moderate liver weight increases accompanied by CYP3A induction were seen in 300 and 900 mg/kg/day rats but not in monkeys or in vitro human hepatocytes. One 450 mg/kg/day monkey died early at day 23 with apparent myelosuppression characterized by atrophy of thymus and spleen, and the relevance to the action of SPH3127 remained unclear. Most of the treatment-induced effects were reversible upon discontinuation of treatment. The no-observed-adverse-effect level (NOAEL) of SPH3127 was determined to be 30 mg/kg/day for Sprague-Dawley rats and 20 mg/kg/day for cynomolgus monkeys based on the kidney and cardiovascular changes found at mid- and high-dose animals.

Renin Activity in Heart Failure with Reduced Systolic Function-New Insights.

Regardless of the cause, symptomatic heart failure (HF) with reduced ejection fraction (rEF) is characterized by pathological activation of the renin-angiotensin-aldosterone system (RAAS) with sodium retention and extracellular fluid expansion (edema). Here, we review the role of active renin, a crucial, upstream enzymatic regulator of the RAAS, as a prognostic and diagnostic plasma biomarker of heart failure with reduced ejection fraction (HFrEF) progression; we also discuss its potential as a pharmacological bio-target in HF therapy. Clinical and experimental studies indicate that plasma renin activity is elevated with symptomatic HFrEF with edema in patients, as well as in companion animals and experimental models of HF. Plasma renin activity levels are also reported to be elevated in patients and animals with rEF before the development of symptomatic HF. Modulation of renin activity in experimental HF significantly reduces edema formation and the progression of systolic dysfunction and improves survival. Thus, specific assessment and targeting of elevated renin activity may enhance diagnostic and therapeutic precision to improve outcomes in appropriate patients with HFrEF.

Efficacy and Safety of Imarikiren in Patients with Type 2 Diabetes and Microalbuminuria: A Randomized, Controlled Trial.

BACKGROUND AND OBJECTIVES: Imarikiren is a novel, potent, and selective direct renin inhibitor that has shown high oral availability during clinical development for the treatment of diabetic nephropathy. We evaluated the efficacy and safety of imarikiren in patients with type 2 diabetes mellitus and microalbuminuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a randomized, multicenter, placebo-controlled, double-blind, phase 2, dose-finding trial. A total of 415 patients were randomized to imarikiren 5, 20, 40, or 80 mg; placebo; or candesartan cilexetil 8 mg treatment for 12 weeks. The primary end point was change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment analyzed using analysis of covariance and a fixed sequence testing procedure. Secondary efficacy end points included urine albumin-to-creatinine ratio at each assessment point and remission and progression rates. Exploratory efficacy end points included eGFR and sitting BP before dosing. RESULTS: Changes in the urine albumin-to-creatinine ratio from baseline to the end of treatment were 16% (placebo), -16% (imarikiren 5 mg), -27% (imarikiren 20 mg), -38% (imarikiren 40 mg), -39% (imarikiren 80 mg), and -31% (candesartan cilexetil 8 mg). Urine albumin-to-creatinine ratio reductions from baseline were statistically significant in all imarikiren groups versus placebo (P<0.001 each) as well as for candesartan cilexetil 8 mg versus placebo (P<0.001). Remission rates (urine albumin-to-creatinine ratio <30 mg/g creatinine and decreased ≥30% from baseline) were higher in all imarikiren groups versus the placebo group. Incidence of adverse events was higher in the imarikiren 80-mg group (52%) versus placebo (42%) and candesartan cilexetil (43%) groups. Incidence of adverse events for the other imarikiren groups ranged from 33% to 42%. Adverse events were mild or moderate in severity. All imarikiren doses were well tolerated. CONCLUSIONS: Imarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria.

Benchmarking renin suppression and blood pressure reduction of direct renin inhibitor imarikiren through quantitative systems pharmacology modeling.

Multiple classes of antihypertensive drugs inhibit components of the renin-angiotensin-aldosterone system (RAAS). The primary physiological effector of the RAAS is angiotensin II (AngII) bound to the AT1 receptor (AT1-bound AngII). There is a strong non-linear feedback from AT1-bound AngII on renin secretion. Since AT1-bound AngII is not readily measured experimentally, plasma renin concentration (PRC) and/or activity (PRA) are typically measured to indicate RAAS suppression. We investigated the RAAS suppression of imarikiren hydrochloride (TAK-272; SCO-272), a direct renin inhibitor currently under clinical development. We employed a previously developed quantitative system pharmacology (QSP) model to benchmark renin suppression and blood pressure regulation with imarikiren compared to other RAAS therapies. A pharmacokinetic (PK) model of imarikiren was linked with the existing QSP model, which consists of a mechanistic representation of the RAAS pathway coupled with a model of blood pressure regulation and volume homeostasis. The PK and pharmacodynamic effects of imarikiren were calibrated by fitting drug concentration, PRA, and PRC data, and trough AT1-bound AngII suppression was simulated. We also prospectively simulated expected mean arterial pressure reduction in a cohort of hypertensive virtual patients. These predictions were benchmarked against predictions for several other (previously calibrated) RAAS monotherapies and dual-RAAS therapies. Our analysis indicates that low doses (5-10 mg) of imarikiren are comparable to current RAAS therapies, and at higher doses (25-200 mg), RAAS suppression may be equivalent to existing dual-RAAS combinations (at registered doses). This study illustrates application of QSP modeling to predict phase II endpoints from phase I data.

A Randomized, Single-Center, Double-Blind, Placebo-Controlled Multiple-Dose Phase 1 Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Imarikiren in Healthy Adult Nonelderly and Elderly Male Subjects.

Imarikiren hydrochloride (TAK-272/ SCO-272) is a novel direct renin inhibitor. This randomized, double-blind, phase I study evaluated the safety and pharmacokinetics/pharmacodynamics of multiple oral administrations of imarikiren in healthy nonelderly (aged 20-45 years) and elderly (aged 65-85 years) Japanese male subjects. Subjects were randomized within 1 of 3 cohorts to receive imarikiren or placebo: Cohort 1 (imarikiren 80 mg; nonelderly), Cohort 2 (imarikiren 160 mg; nonelderly), or Cohort 3 (imarikiren 80 mg; elderly). Imarikiren or placebo was administered orally, once daily, for 7 days. Accumulation of imarikiren did not occur during the 7-day treatment period. Area under the plasma-concentration time curve and maximum plasma concentration of imarikiren were higher in elderly than in nonelderly subjects (52% and 39% higher, respectively). Inhibition of plasma renin activity was observed for 7 days and was maintained for at least 71 hours after the last imarikiren administration at the 80-mg (nonelderly and elderly) and 160-mg (nonelderly) doses. Plasma active renin concentration increased in nonelderly and elderly subjects; peak concentrations were higher on day 7 than on day 1. Increase from baseline in plasma active renin concentration was smaller in elderly than in nonelderly subjects during the 7-day treatment period and until 71 hours after last imarikiren administration. Treatment-emergent adverse events were reported in 33.3% (elderly) and 22.2% (nonelderly) of imarikiren subjects. Multiple oral administrations of imarikiren for 7 days were safe and well tolerated with no drug accumulation and strong and sustained suppression of plasma renin activity.

Combination Therapy of Renin Angiotensin System Inhibitors and ß-Blockers in Patients with Heart Failure.

Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system play crucial roles in heart failure with reduced ejection fraction (HFrEF). Clinical trials provide strong evidence of prognostic benefits for combination therapy with angiotensin-converting enzyme inhibitor (ACEI) and ß-blocker in the treatment of HFrEF. Angiotensin receptor blocker (ARB) is not superior to ACEI in improving mortality and an alternative for patients who are intolerant to ACEI. Prognostic evidence for triple therapy which combined angiotensin receptor blocker (ARB) and ACEI in addition to ß-blocker therapy, is still controversial in HFrEF. Moreover, a recent clinical trial showed that triple therapy did not provide additional benefit compared with ACEI or ARB therapy alone in mildly symptomatic HFrEF. Of note, the triple therapy can even cause harm and renal dysfunction in HF with a history of hypertension. Direct renin inhibitor (DRI) has the theoretical benefit of upstream RAAS inhibition at the point of pathway activation. However, the results from clinical trials do not support upstream renin inhibition by DRI in addition to standard therapy with ACEI in patients with HFrEF. Angiotensin receptor-neprilysin inhibitor (ARNI) which combines a neprilysin inhibitor and ARB valsartan have a unique mode of action targeting both RAAS and the natriuretic peptide systems. In contrast to the evidence in HFrEF, clinical value of combination therapy with RAAS inhibitors and ß-blocker is not well established in HF with preserved EF (HFpEF). The heterogeneity of diagnostic criteria and baseline characteristics of HFpEF need further evidence for the combination therapy. However, a recent clinical trial of LCZ696 showed promising results in reducing NT-proBNP in patients with HFpEF.

Direct renin inhibition is not enough to prevent reactive oxygen species generation and vascular dysfunction in renovascular hypertension.

Renin-angiotensin system activation promotes oxidative stress and endothelial dysfunction. However, no previous study has examined the effects of the renin inhibitor aliskiren, either alone or combined with angiotensin II type 1 antagonists on alterations induced by two-kidney, one-clip (2K1C) hypertension. We compared the vascular effects of aliskiren (50mg/kg/day), losartan (10mg/kg/day), or both by gavage for 4 weeks in 2K1C and control rats. Treatment with losartan, aliskiren, or both exerted similar antihypertensive effects. Aliskiren lowered plasma Ang I concentrations in sham rats and in hypertensive rats treated with aliskiren or with both drugs. Aliskiren alone or combined with losartan decreased plasma angiotensin II concentrations measured by high performance liquid chromatography, whereas losartan alone had no effects. In contrast, losartan alone or combined with aliskiren abolished hypertension-induced increases in aortic angiotensin II concentrations, whereas aliskiren alone exerted no such effects. While hypertension enhanced aortic oxidative stress assessed by dihydroethidium fluorescence and by lucigenin chemiluminescence, losartan alone or combined with aliskiren, but not aliskiren alone, abolished this alteration. Hypertension impaired aortic relaxation induced by acetylcholine, and losartan alone or combined with aliskiren, but not aliskiren alone, reversed this alteration. Losartan alone or combined with aliskiren, but not aliskiren alone, increased plasma nitrite concentrations in 2K1C rats. These findings show that antihypertensive effects of aliskiren do not prevent hypertension-induced vascular oxidative stress and endothelial dysfunction. These findings contrast those found with losartan and suggest that renin inhibition is not enough to prevent hypertension-induced impaired redox biology and vascular dysfunction.

Effects of aliskiren on mortality, cardiovascular outcomes and adverse events in patients with diabetes and cardiovascular disease or risk: A systematic review and meta-analysis of 13,395 patients.

BACKGROUND: Aliskiren was shown to increase adverse events in patients with diabetes and concomitant renin-angiotensin blockade. We aim to investigate the efficacy and safety of aliskiren in patients with diabetes and increased cardiovascular risk or established cardiovascular disease. METHODS: MEDLINE and Embase were searched for prospective studies comparing addition of aliskiren to standard medical therapy in patients with diabetes and cardiovascular disease, or ⩾1 additional cardiovascular risk factor (hypertension, abnormal lipid profile, microalbuminuria/proteinuria, chronic kidney disease). Relative risk for efficacy (all-cause mortality, combined cardiovascular mortality and hospitalisation) and safety (hyperkalaemia, hypotension, renal impairment) outcomes was calculated. RESULTS: Of 2151 studies identified in the search, seven studies enrolling 13,395 patients were included. Aliskiren had no effect on all-cause mortality (relative risk: 1.05, 95% confidence interval: 0.90 to 1.24, p = 0.53), or combined cardiovascular mortality or heart failure hospitalisation (relative risk: 1.07, 95% confidence interval: 0.81 to 1.40, p = 0.64). Patients receiving aliskiren had a greater risk of developing hyperkalaemia (relative risk: 1.32, 95% confidence interval: 1.14 to 1.53, p = 0.0003) and renal impairment (relative risk: 1.15, 95% confidence interval: 1.02 to 1.30, p = 0.03), but not hypotension. CONCLUSION: Patients with diabetes and cardiovascular disease or cardiovascular risk do not benefit from the addition of aliskiren to standard medical therapy. Detrimental safety profile in pooled analysis supports current warnings.

Successful long-term effects of direct renin inhibitor aliskiren in a patient with atherosclerotic renovascular hypertension.

A 64-year-old man visited our hospital with complaints of misty vision and ophthalmalgia. On admission, his blood pressure (BP) was high at 220/135 mmHg with no past history of hypertension, and he had choked discs. He was tentatively diagnosed as having idiopathic intracranial hypertension, and was later found to have atherosclerotic unilateral renovascular hypertension (RVH) based upon the extremely high plasma renin activity together with the radiological image tests. On day 3, combined antihypertensive therapies consisting of oral angiotensin II receptor blocker (ARB) and Ca channel blocker (CCB) along with intravenous CCB induced an abrupt BP lowering which led to deterioration of his renal function, progressing into acute kidney injury (AKI). Cessation of the ARB and reduction of the CCB dose ameliorated the AKI-related decline in renal function. On day 17, as he was reluctant to receive surgical intervention, he was treated with a direct renin inhibitor, aliskiren, combined with a half-dose CCB as a maintenance antihypertensive therapy. The therapy has proven not only successful to chronically maintain his renal function but was also capable of controlling his BP in the neighborhood of 130/85 mmHg over a period of 2 years. The present case suggests that the direct renin inhibition with aliskiren can be a safe and useful antihypertensive option to control hypertension and to preserve renal function in patients with atherosclerotic unilateral RVH.

Aliskiren increases aquaporin-2 expression and attenuates lithium-induced nephrogenic diabetes insipidus.

The direct renin inhibitor aliskiren has been shown to be retained and persist in medullary collecting ducts even after treatment is discontinued, suggesting a new mechanism of action for this drug. The purpose of the present study was to investigate whether aliskiren regulates renal aquaporin expression in the collecting ducts and improves urinary concentrating defect induced by lithium in mice. The mice were fed with either normal chow or LiCl diet (40 mmol·kg dry food-1·day-1 for 4 days and 20 mmol·kg dry food-1·day-1 for the last 3 days) for 7 days. Some mice were intraperitoneally injected with aliskiren (50 mg·kg body wt-1·day-1 in saline). Aliskiren significantly increased protein abundance of aquaporin-2 (AQP2) in the kidney inner medulla in mice. In inner medulla collecting duct cell suspension, aliskiren markedly increased AQP2 and phosphorylated AQP2 at serine 256 (pS256-AQP2) protein abundance, which was significantly inhibited both by adenylyl cyclase inhibitor MDL-12330A and by PKA inhibitor H89, indicating an involvement of the cAMP-PKA signaling pathway in aliskiren-induced increased AQP2 expression. Aliskiren treatment improved urinary concentrating defect in lithium-treated mice and partially prevented the decrease of AQP2 and pS256-AQP2 protein abundance in the inner medulla of the kidney. In conclusion, the direct renin inhibitor aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus likely via cAMP-PKA pathways.

Comparison of direct renin inhibitor and angiotensin II receptor blocker on clinic and ambulatory blood pressure profiles in hypertension with chronic kidney disease.

We compared the therapeutic effects of aliskiren (direct renin inhibitor (DRI) group) with angiotensin II (Ang II) type 1 receptor blockers (ARBs) (ARB group) on clinic blood pressure (BP) and ambulatory BP in 36 hypertensive chronic kidney disease (CKD) patients. The baseline clinic BP levels and the after-treatment/baseline (A/B) ratios of clinic BP levels, estimated after 24-week treatment period, were similar in DRI group (n = 18) and ARB group (n = 18). With respect to the effects on ambulatory BP, the A/B ratios of the daytime and nighttime systolic BP in DRI group were significantly higher than those in ARB group. The A/B ratio of ankle-brachial pressure index after the study was higher in the DRI group compared with the ARB group. The results of the present study suggest that DRI therapy is not superior to ARB therapy in lowering ambulatory BP in hypertensive CKD patients, in spite of comparable clinic BP-lowering effects.

Efficacy and Safety of Complete RAAS Blockade with ALISKIREN in Patients with Refractory Proteinuria Who were already on Combined ACE Inhibitor, ARB, and Aldosterone Antagonist.

INTRODUCTION: Proteinuria is always associated with intrinsic kidney disese and is a strong predictor of later development of End Stage Renal Disease (ESRD). As Renin Angiotensin Aldosterone System (RAAS) has a role in mediating proteinuria, inhibitors of this system are renoprotective and patients with refractory proteinuria are put on a combination of these agents. The routinely employed triple blockade of RAAS with Angiotensin Converting Enzyme (ACE) inhibitor, ARB and Aldosterone antagonist has many limitations. Addition of Aliskiren to this combination suppresses the RAAS at the earliest stage and can offset many of these limitations. AIM: This study was conducted to assess the safety and efficacy of complete RAAS blockade by the addition of Aliskiren in those patients with refractory proteinuria who were already on triple blockade with ACE inhibitor, ARB and Aldosterone antagonist. SETTINGS: This study was conducted in Nephrology Department, Calicut Medical College. MATERIALS AND METHODS: A total of 36 patients with refractory proteinuria who were already on ACE inhibitor, ARB and Aldosterone antagonist were divided in to two groups A and B. Group A received Aliskiren in addition to the above combination whereas group B continued the same treatment for 12 weeks. Efficacy of the treatment was assessed by recording 24hr urine protein and safety by S.Creatinine, S.Potassium every 2 weeks of the treatment period. STATISTICAL ANALYSIS: Statistical analysis of the lab values was done using SPSS software. Unpaired t-test, Paired t-test and Chi-square test were done for data analysis. RESULTS: Statistical analysis revealed that addition of Aliskiren to the combination therapy with ACE inhibitor+ ARB+ Aldosterone antagonist offers no advantage. But mean reduction in proteinuria was more with Group A than Group B. There is no statistically significant change in S.Creatinine and S.Potassium at the end of treatment. CONCLUSION: As proteinuria is a strong risk factor for progression to ESRD, even a mild decrease in proteinuria by treatment is renoprotective. Hence treatment with group A may be considered clinically superior to group B with no alteration in safety and tolerability. But further multicentre studies with larger sample size and dose escalation are required for confirmation.

Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice.

Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress.

Efficacy of aliskiren, compared with angiotensin II blockade, in slowing the progression of diabetic nephropathy in db/db mice: should the combination therapy be a focus?

Although the intensive use of angiotensin II blockade (ACEI or ARB), progression of diabetic nephropathy is common. A feedback increase in renin production often accompanies angiotensin II blockade. We therefore examined whether aliskiren, a direct renin inhibitor, confers better renoprotection than angiotensin II blockade and whether the addition of aliskiren to an ACEI or ARB would enhance the efficacy in slowing the progression of glomerulosclerosis in diabetes. Untreated db/db mice developed progressive mesangial matrix expansion and albuminuria between weeks 18 and 22, associated with reduction of WT-1 immunopositive podocytes and nephrin and podocin production and induction of desmin and B7-1 generation and renal expression of TGFß1, PAI-1, fibronectin and type IV collagen. Treatment with aliskiren at 30 mg/kg/d inhibited the increases in albuminuria and markers of renal fibrosis and the changes that are indicative of podocyte injury seen in the db/db mice. Notably, the therapeutic effect of aliskiren was similar to that of either enalapril or valsartan given alone at maximally effective doses. Combined therapy caused the loss of 10% ~ 16.6% of db/db mice, yielded no further reduction in renal fibrosis and podocyte injury but further reduced albuminuria and renal production of TNFα, Nox2 and p47phox and urine MCP-1 and malondialdehyde levels, the markers of renal inflammation and oxidative stress. These results suggest that aliskiren, enalapril and valsartan are equally effective in slowing the progression of diabetic nephropathy. The use of combination therapy with aliskiren and ACEI/ARB may not be strongly supported.