Renin-angiotensin-aldosterone System Blockade Research Articles

Comparative proteomic analysis of rat left ventricle in a subtotal nephrectomy model

BackgroundChronic kidney disease (CKD) is associated with cardiac hypertrophy that leads to increased cardiovascular morbidity and mortality. To date, use of the renin–angiotensin–aldosterone system blockade has been the main treatment modality. However, renin–angiotensin–aldosterone system blockade by the angiotensin converting enzyme inhibitors (ACEi) can only partially reverse the cardiac hypertrophy without having a significant impact on all-cause mortality as evidenced by meta-analyses from clinical trials. It is imperative to elucidate the molecular pathogenesis of CKD-related cardiomyopathy for potential targets in further treatment. MethodsMale Sprague–Dawley rats that underwent subtotal nephrectomy (SNX) rats were established as the CKD model. A hemodynamic study was used to evaluate the left ventricle (LV) structural and functional alterations. We used proteomic techniques to profile the LV protein changes among sham-operated rats, SNX rats, and SNX rats with 6 months of ACEi enalapril interventions. The differentially expressed proteins were further annotated by functional and network analyses. ResultsAs compared to the sham-operated rats, the SNX rats had 25 upregulated and 46 decreased protein expression. The top canonical pathways identified by ingenuity pathway analysis for the CKD cardiomyopathy were mitochondrial dysfunction, oxidative phosphorylation, fatty acid β oxidation, protein ubiquitination, and ketolysis. The most relevant functions extracted from these networks contained 27 and 23 focused proteins, respectively. They were related to cellular assembly and organization, RNA posttranscriptional modification, and protein synthesis. After ACEi intervention for 6 weeks, the residual canonical pathways identified by ingenuity pathway analysis that mediated the CKD-related cardiomyopathy were mitochondrial dysfunction, ketolysis, phenylalanine degradation IV, and putrescine degradation III. There were decreased Sirt3 and SNRNP, and increased monoamine oxidase and SAHH expression in the LV of SNX rats that could not be reversed by the ACEi. ConclusionOur studies provide a repertoire of potential biomarkers related to cardiac hypertrophy in CKD. There are still residual disturbed molecules/pathways despite ACEi intervention. Further studies are warranted to investigate these potential novel targets to alleviate CKD-related cardiomyopathy.

Dual renin-angiotensin-aldosterone blockade: promises and pitfalls.

Single renin-angiotensin-aldosterone system (RAAS) blockade has been shown to be effective and safe for the treatment of hypertension, coronary heart disease (CHD), heart failure (HF), diabetes, and chronic kidney disease (CKD) with proteinuria. Due to the action of RAAS blockers at various levels of the RAAS cascade, it was hypothesized that dual RAAS blockade would result in more complete inhibition of angiotensin II (Ang II) production and be more effective in blocking its detrimental cardiovascular remodeling effects. Unfortunately, several clinical trials in patients with hypertension, CHD, HF, and CKD with proteinuria have demonstrated no superiority of dual versus single RAAS blockade, but a higher incidence of adverse events. Based on these findings, dual RAAS blockade is no longer recommended for the routine treatment of various cardiovascular diseases, except diabetic nephropathy with proteinuria and HF with reduced ejection fraction. All the new information gathered from studies within the last 3years will be presented in this review.

A randomized control trial to assess the impact of vitamin D supplementation compared to placebo on vascular stiffness in chronic kidney disease patients.

BackgroundVitamin D deficiency is associated with cardiovascular (CV) risk in multiple populations, including those with chronic kidney disease (CKD). The active form of the hormone (1,25 OH2D3) binds to receptors in multiple organs. CKD patients are deficient in both 25 Vitamin D and 1,25 OH2D3. Clinical trial data demonstrating the benefits of vitamin D formulations are limited, and fail to show significant benefits on CV outcomes, and have compared different compounds, in various populations, and focused on a variety of outcomes. A understanding of the mechanism by which different vitamin D compounds confer CV protection in CKD is important for the design of future studies.Methods/DesignThis 3 arm randomized prospective double-blinded placebo-controlled study examining the impact of calcitriol (1,25 OH2D3) and 25-hydroxyvitamin D3 supplementation compared to placebo on vascular stiffness, as measured by pulse wave velocity (PWV). Patients are enrolled from 2 tertiary care institutions if they meet inclusion criteria (stable estimated glomerular filtration rate (eGFR) between 15-45ml/min, <±5ml/min change in previous 6 months), on stable doses of renin-angiotensin aldosterone system blockade. For those already receiving vitamin D therapies, a 3 month washout period before randomization is mandatory. Treatment duration is 6 months; medications are given thrice weekly in fixed doses. The primary outcome measure is Vascular stiffness, measured non-invasively by pulse wave velocity (PWV). Other measurements include BP, kidney function and serial blood levels of biomarkers. The primary analysis will compare any vitamin D therapy versus placebo for the primary outcome defined as the change of PWV from baseline to 6 months. Analysis of covariance will be used to detect differences between vitamin D preparations in the magnitude of reduction in PWV.DiscussionThis study is novel in that we are using a robust study design in CKD patients (not on dialysis) comparing placebo to different forms of vitamin D supplementation in fixed doses, irrespective of baseline values. We hope to demonstrate the biological mechanistic effect of vitamin D supplementation on vascular function in order for this information to be used in designing larger randomized controlled trials.Trial registrationCurrent Controlled Trials NCT01247311. Date of Registration: November 12, 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2261-14-156) contains supplementary material, which is available to authorized users.

Vitamin D analogue therapy, cardiovascular risk and kidney function in people with Type 1 diabetes mellitus and diabetic nephropathy: a randomized trial.

To evaluate the effects of therapy with the vitamin D analogue paricalcitol on markers of cardiovascular risk and kidney function in people with Type 1 diabetes mellitus and diabetic nephropathy. In a double-blind, randomized placebo-controlled, crossover trial, 48 participants on stable renin angiotensin aldosterone system blockade and diuretics were assigned, in random order, to 12weeks of paricalcitol and 12weeks of placebo therapy, separated by a 4-week washout period. Primary and secondary endpoints were changes in plasma N-terminal probrain natriuretic peptide and urinary albumin excretion rate obtained before and after each intervention. Glomerular filtration rates were estimated and measured ((51) Cr-EDTA plasma clearance glomerular filtration rate) after each intervention. The mean (sd) age of the participants was 57 (9) years, the baseline geometric mean (95% CI) urinary albumin excretion rate was 148 (85-259) mg/24h, the mean (sd) HbA1c was 70 (9) mmol/mol [8.6 (3)%], the mean (sd) estimated glomerular filtration rate was 47 (15) ml/min/1.73m(2) and the mean (sd) 24-h blood pressure was 135 (17)/74 (10) mmHg. Compared with placebo therapy, vitamin D analogue therapy had no significant effect on plasma N-terminal probrain natriuretic peptide concentration (P=0.6), urinary albumin excretion rate was reduced by 18% (P=0.03 for comparison), estimated glomerular filtration rate was reduced by 5ml/min/1.73m(2) (P<0.001) and measured glomerular filtration rate was reduced by 1.5ml/min/1.73m(2) (P=0.2). Paricalcitol therapy did not affect plasma N-terminal probrain natriuretic peptide concentration in people with Type 1 diabetes and diabetic nephropathy; however, the urinary albumin excretion rate was significantly lowered.

Renin blockade: a double-edged sword?

Aliskiren, a direct renin inhibitor, blocks the first step of the renin–angiotensin–aldosterone system (RAAS), thereby reducing plasma renin activity and the circulating levels of angiotensin I, angiotensin II, and aldosterone. Extensive RAAS blockade can be achieved through the administration of aliskiren; however, renin blockade is a double-edged sword because the renin/prorenin receptor-associated pathway is also reportedly modulated by direct renin inhibitor. This research highlight discusses the findings of a recent clinical study of aliskiren and explores the complex interactions of key molecules in the RAAS pathway in response to aliskiren administration.

Improved prognosis following renin–angiotensin–aldosterone system blockade in patients undergoing concomitant aortic and mitral valve replacement

Improved prognosis following renin–angiotensin–aldosterone system blockade in patients undergoing concomitant aortic and mitral valve replacement

Complete inhibition of the renin-angiotensin-aldosterone system; where do we stand?

This review presents the role of combination therapy of renin-angiotensin-aldosterone system blockade on cardiovascular and kidney disease. Three large randomized controlled trials comparing combination therapy of renin-angiotensin-aldosterone system blockade to monotherapy in individuals with increased cardiovascular risk, chronic kidney disease, or diabetic nephropathy have been reported. These trials - ONTARGET, ALTITUDE, and VA NEPHRON-D - demonstrated an excess risk of adverse effects [especially acute kidney injury (AKI) and hyperkalemia] with combination therapy, without significant benefit in reducing cardiovascular and renal morbidity. Current evidence supports avoiding dual renin-angiotensin-aldosterone system blockade in patients with chronic kidney disease. Subsequent studies of dual renin-angiotensin-aldosterone system blockade should examine adverse event risks and renal progression endpoints.

Worsening Renal Function and Outcome in Heart Failure Patients With Preserved Ejection Fraction and the Impact of Angiotensin Receptor Blocker Treatment

BackgroundWorsening renal function (WRF) associated with renin-angiotensin-aldosterone system (RAAS) inhibition does not confer excess risk in heart failure patients with reduced ejection fraction (HFrEF). ObjectivesThe goal of this study was to investigate the relationship between WRF and outcomes in heart failure patients with preserved ejection fraction (HFpEF) and the interaction with RAAS blockade. MethodsIn 3,595 patients included in the I-PRESERVE (Irbesartan in Heart Failure With Preserved Ejection Fraction) trial, change in estimated glomerular filtration rate (eGFR) and development of WRF after initiation of irbesartan or placebo were examined. We examined the association between WRF and the first occurrence of cardiovascular death or heart failure hospitalization (primary outcome in this analysis) and the interaction with randomized treatment. ResultsEstimated GFR decreased early with irbesartan treatment and remained significantly lower than in the placebo group. WRF developed in 229 (6.4%) patients and occurred more frequently with irbesartan treatment (8% vs. 4%). Overall, WRF was associated with an increased risk of the primary outcome (adjusted hazard ratio [HR]: 1.43; 95% confidence interval [CI]: 1.10 to 1.85; p = 0.008). Although the risk related to WRF was greater in the irbesartan group (HR: 1.66; 95% CI: 1.21 to 2.28; p = 0.002) than with placebo (HR: 1.09; 95% CI: 0.66 to 1.79; p = 0.73), the interaction between treatment and WRF on outcome was not significant in an adjusted analysis. ConclusionsThe incidence of WRF in HFpEF was similar to that previously reported in HFrEF but more frequent with irbesartan than with placebo. WRF after initiation of irbesartan treatment in HFpEF was associated with excess risk, in contrast to WRF occurring with RAAS blockade in HFrEF.

Aldosterone blockade as an alternative renin-angiotensin-aldosterone system blocking agent in cases of treatment associated anemia

Blockade of the renin-angiotensin-aldosterone system (RAAS) is a mainstay of therapy for proteinuric kidney disease due to effects on blood pressure, proteinuria, and overall cardiovascular risk. In this case series, we highlight one of the rare but serious side effects of the most commonly used RAAS blocking drugs, angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs): a severe anemia due to impaired erythropoiesis. The four patients presented here were switched to a mineralocorticoid receptor blocker (MRB) that targets aldosterone without any inhibition of angiotensin II, and resulting in significant rebounds back to baseline hemoglobin levels. Furthermore, all patients had optimal blood pressure control and proteinuria reductions. These data support the use of aldosterone blocking agents in kidney disease patients with anemia secondary to ACE-Is or ARB. Presumably, any patient - regardless of kidney status - for whom RAAS blockade is indicated (e.g., diabetic patients or patients with congestive heart failure) should be switched to MRB therapy if significant anemia develops after starting an ACE-Is or ARB.

An ACE in the Hole for Patients With Advanced Chronic Kidney Disease?

In the treatmentofpatientswithadvancedchronickidneydisease (CKD) (which can be considered present when the estimated glomerular filtration rate [GFR] falls to <20 mL/min/ 1.73m2 and individuals become eligible to accrue time on the kidney transplant waiting list in the United States), a paramount goal is preventing or retarding progression to endstage renal disease and the requirement of dialysis. At earlier stages of CKD, blockade of the renin-angiotensinaldosteronesystem(RAAS) is amainstay therapy; angiotensinconverting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) clearly slow renal function decline, especially among thosewith proteinuria. However, the use of ACEIs or ARBs in advanced CKD remains uncertain. This important clinical question is the subject of a new study by Hsu and colleagues.1 Physiciansmayhesitate to prescribeACEIs or ARBs in advanced CKD for several reasons. Angiotensin-converting enzymeinhibitorsandARBs increaseserumpotassiumlevels, and their use in advanced CKDmay lead to dangerous hyperkalemia. InitiationofRAASblockade isoftenassociatedwithshorttermreductions inGFR,asmuchas30%.This reduction is generally believed to be due to reductions in intraglomerular pressure, hemodynamically reversible and self-limited (unless there are unusual coexisting conditions, such as severe renal artery stenosis).2,3 However, in advancedCKD, a 30% difference in GFR may determine whether the patient needs immediate initiation of dialysis. There have also been reports of substantial increase in GFR (more than 30%) after cessation of ACEI or ARB therapy in advanced CKD, resulting in postponement of dialysis.4 Other investigatorshaveemphasized that theuseofACEIs andARBsheightens the riskof acute-on-chronic renal failure.5 PatientswithCKDareat increased risk for acutekidney injury,6 andnumerouspatientswithmoderateoradvancedCKDdonot recover fromanepisodeof dialysis-requiring acute kidney injury but instead become dependent on long-term dialysis. Therefore, a superimposed episodeof severe acute kidney injury can immediately precipitate end-stage renal disease in some CKD patients.7 Thus, although somedata from randomized clinical trials suggest that RAAS blockade can be implemented safely and is efficacious in advanced CKD,8,9 much uncertainty remains about use of ACEIs andARBs in non–clinical trial participants with advancedCKD,particularly the elderly. The studybyHsu andcolleagues1usesacomprehensiveTaiwanesedatabase that captures health care utilization data of more than 95% of the hospitals in Taiwan and99%of the country’s population of 23 million. The investigators studied 28497patientswith stable, hypertensive, advanced CKD receiving erythropoiesisstimulatingagent (ESA) therapywhohaveserumcreatinine levels greater than 6 mg/dL (to convert to micromoles per liter, multiplyby88.4).Of these, 14 117usedACEIs/ARBs, and14380 werenonusers.UseofACEIs/ARBswasassociatedwitha lower hazard ratio for long-term dialysis (0.94 [95% CI, 0.91-0.97]) andthecompositeoutcomeof long-termdialysisordeath (0.94 [0.92-0.97]). Similar results were seen in several sensitivity analyses. The strengths of this study include its large size and its being nationally representative. The large proportion of patients with diabetes mellitus enhances generalizability because these patientswere excluded fromprior studies.8,9Hsu and colleagues1 provide reassuring information complementing the data from randomized clinical trials that RAAS blockadecanbesafely implementedeven inadvancedCKD.8,9Based on the age and sex distribution provided (more than half the patientswere older than65years and female), all patients had an estimated GFR of 12 mL/min/1.73m2 or less. A large, randomized clinical trial seems unlikely to be undertaken in this subset of patients in the foreseeable future. However, several caveats must be kept in mind when interpreting these data. No information regarding blood pressure,proteinuria,orother importantpatient-level clinical characteristics was provided. Themajor weakness of this study is that the actual levels of renal function were unknown because the database did not contain serum creatinine values. Instead, the level of renal functionwas inferred based onprescription of an ESA. The authors’ claim that the 28 497 patients studied had serum creatinine levels of greater than 6 mg/dL (andhematocrit levels of <28%) is basedonTaiwanNational Health Insurance reimbursement regulations bywhich patients meeting these criteria “could receive ESA treatment tomaintainahematocrit levelnot exceeding36%.”1Thus, confoundingbydifferences in the level ofGFRbetweenusers and nonusers of ACEIs/ARBs is a concern. The strength of the association between the level of GFR and the need for dialysis is very strong,10 at anorder ofmagnitude stronger than the association between the level of GFR and other adverse outcomes, such as cardiovascular disease.11 Hence, if ACEI/ARB users had on average even slightly higher levels of GFR, confounding may account for the rather modest observed effect size (approximately 6%). BlockadeofRAAS is known to lower hematocrit levels in CKDpatients12; hence, use of anESAmay be triggered amongACEI/ARBusers at higher GFR levels than ACEI/ARB nonusers. In addition,patientswithadvancedCKDwhoaremoreadherent to treatment regimens may be more likely to be prescribedACEIs/ARBs because nephrologistsmay trust them to come reliably for follow-up appointments and toundergo freRelated article page 347 Renin-Angiotensin System Blockade in CKD Original Investigation Research

Cushing's disease and hypertension: in vivo and in vitro study of the role of the renin-angiotensin-aldosterone system and effects of medical therapy

Cushing's disease (CD) is often accompanied by hypertension. CD can be treated surgically and, given the expression of somatostatin subtype 5 and dopamine 2 receptors by corticotroph pituitary adenomas, pharmacologically. Indeed, we recently observed that stepwise medical combination therapy with the somatostatin-analog pasireotide, the dopamine-agonist cabergoline, and ketoconazole (which directly suppresses steroidogenesis) biochemically controlled CD patients and lowered their blood pressure after 80 days. Glucocorticoids (GC) modulate the renin-angiotensin-aldosterone system (RAAS) among others by increasing hepatic angiotensinogen expression and stimulating mineralocorticoid receptors (MR). This study therefore evaluated plasma RAAS components in CD patients before and after drug therapy. In addition, we studied whether cabergoline/pasireotide have direct relaxant effects in angiotensin II (Ang II)-constricted iliac arteries of spontaneously hypertensive rats, with and without concomitant GR/MR stimulation with dexamethasone or hydrocortisone. Baseline concentrations of angiotensinogen were elevated, while renin and aldosterone were low and suppressed, respectively, even in patients treated with RAAS-blockers. This pattern did not change after 80 days of treatment, despite blood pressure normalization, nor after 4 years of remission. In the presence of dexamethasone, pasireotide inhibited Ang II-mediated vasoconstriction. The low plasma renin concentrations, even under RAAS blockade, in CD may be the consequence of increased GC-mediated MR stimulation and/or the elevated angiotensinogen levels in such patients. The lack of change in RAAS-parameters despite blood pressure and cortisol normalization suggests persisting consequences of long-term exposure to cortisol excess. Finally, pasireotide may have a direct vasodilating effect contributing to blood pressure lowering.

Syndrome of rapid onset end stage renal disease in incident Mayo Clinic chronic hemodialysis patient

Despite decades of research, a full understanding of chronic kidney disease (CKD)-end stage renal disease (ESRD) progression remains elusive. The common consensus is a predictable, linear, progressive and time-dependent decline of CKD to ESRD. Acute kidney injury (AKI) on CKD is usually assumed to be transient, with recovery as the expected outcome. AKI-ESRD association in current nephrology literature is blamed on the so-called “residual confounding.” We had previously described a relationship between AKI events and rapid onset yet irreversible ESRD happening in a continuum in a high-risk CKD cohort. However, the contribution of the syndrome of rapid onset-ESRD (SORO-ESRD) to incident United States ESRD population remained conjectural. In this retrospective analysis, we analyzed serum creatinine trajectories of the last 100 consecutive ESRD patients in 4 Mayo Clinic chronic hemodialysis units to determine the incidence of SORO-ESRD. Excluding 9 patients, 31 (34%) patients, including two renal transplant recipients, had SORO-ESRD: 18 males and 13 females age 72 (range 50-92) years. Precipitating AKI followed pneumonia (8), acutely decompensated heart failure (7), pyelonephritis (4), post-operative (5), sepsis (3), contrast-induced nephropathy (2), and others (2). Time to dialysis was shortest following surgical procedures. Concurrent renin angiotensin aldosterone system blockade was higher with SORO-ESRD - 23% versus 5%, P = 0.0113. In conclusion, SORO-ESRD is not uncommon among the incident general US ESRD population. The implications for ESRD care planning, AV-fistula-first programs, general CKD care and any associations with renal ageing/senescence warrant further study.

Hypertension in Metabolic Syndrome-An Overview

Metabolic syndrome is a cluster of insulin resistance (IR), obesity, dyslipidemia. Hypertension, hyperglycemia and vascular disorders. Hypertension(HTN) is a very prominent component of the metabolic syndrome(Mets), present in up to 85% of patients. HTN is a very common condition which frequently remains silent and undiagnosed till late in its course. The establishment of HTN as a component of the metabolic syndrome has enabled better insight into the condition. HTN is associated with the laboratory and anthropometric findings linked to the Mets. IR and central obesity, recognized as the main factors linked with pathophysiology of the Mets, contribute to HTN which further promotes vascular damage in cardiac, renal, eye and brain tissue. IR and the resulting hyperinsulinemia induce blood pressure elevation by the activation of sympathetic nervous system(SNS) and renin-angiotensin-aldosterone system (RAAS) with consequential sodium retention and volume expansion, endothelial dysfunction and alteration in renal function. Visceral fat, in comparison to subcutaneous tissue, represents a metabolically active organ, strongly related to insulin sensitivity. One of the proposed mechanisms by which hypertension is linked with central obesity includes sympathetic SNS overactivation. There is strong link between vasoconstriction due to IR and HTN as per insulin hypothesis of hypertension in Mets. Therapeutic approach to patients with HTN and Mets includes modification of unhealthy lifestyle which includes sodium, alcohol and calorie restriction, smoking cessation, weight reduction and increased physical activity. However, it is often insufficient to obtain the target values of blood pressure. Concerning pharmacological agents, emphasis is in particular placed on the RAAS blockade with angiotensin converting enzyme(ACE) inhibitors, angiotensin II receptor blockers(ARB) and on central sympatholytic agents that exert additional beneficial effects. An overview of hypertension in metabolic syndrome has been attempted in this review article.

Sodium restriction on top of renin–angiotensin–aldosterone system blockade increases circulating levels of N-acetyl-seryl-aspartyl-lysyl-proline in chronic kidney disease patients

Sodium restriction potentiates the efficacy of the rennin-angiotensin-aldosterone system (RAAS)-blockade and improves long-term cardiovascular and renal protection, even independent of the better blood pressure control. The mechanisms underlying the potentiation of cardiorenal protection by sodium restriction are incompletely understood. RAAS-blockade with angiotensin-converting enzyme (ACE) inhibitors increases circulating levels of the anti-inflammatory and antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), which is assumed to contribute to its therapeutic effects. We hypothesized that sodium restriction on top of RAAS-blockade further increases AcSDKP, as a possible explanation for the enhanced effects of RAAS-blockade during sodium restriction. To test this hypothesis, we performed a secondary analysis of a randomized clinical trial investigating 46 nondiabetic chronic kidney disease (CKD) patients (age 50±13 years, 80% men) with overt proteinuria and mild to moderate renal insufficiency. Patients were subjected, in a crossover design, to four double-blind 6-week study periods with either regular sodium diet (194±49 mmol Naday) or low sodium diet (102±52 mmol Na/day) on top of either lisinopril (40 mg/day; single RAAS-blockade) or lisinopril plus valsartan (320 mg/day; dual RAAS-blockade). Sodium restriction significantly increased circulating levels of AcSDKP during single and dual RAAS-blockade (P=0.032 and 0.042, respectively). Linear mixed-model analysis confirmed that AcSDKP levels were increased in response to sodium restriction, irrespective of sex, age, creatinine clearance, blood pressure, BMI, single or dual RAAS-blockade, treatment sequence and other dietary factors, that is calcium and protein (P=0.020). In patients with nondiabetic CKD, we demonstrated that sodium restriction, on top of single and dual RAAS-blockade, increases circulating levels of the anti-inflammatory and antifibrotic peptide AcSDKP. The rise in AcSDKP may contribute to the increased protection of RAAS-blockade during sodium restriction.

Interaction between baseline and early worsening of renal function and efficacy of renin–angiotensin–aldosterone system blockade in patients with heart failure: insights from the Val‐HeFT study

We evaluated the effect of (dual) renin-angiotensin-aldosterone system (RAAS) blockade with valsartan and an ACE inhibitor [92.7% of patients were treated with an ACE inhibitor in the Valsartan in Heart Failure Trial (Val-HeFT)] in patients with NYHA class II-IV heart failure (HF) and reduced EF on cardiovascular (CV) death and HF hospitalization by subgroups and by presence of early worsening of renal function (EWRF) and according to baseline estimated glomerular filtration rate (eGFR). We analysed the data from 5010 patients enrolled in the Val-HeFT study. A total of 2346 (46.8%) patients had baseline renal impairment (i.e. baseline eGFR <60 mL/min/1.73 m(2)). Further, 425 patients (8.6%) had EWRF (i.e. eGFR decrease >20% within 1 month after randomization), whereas 4503 patients (91.4%) had ≤20% decline in eGFR. Overall, the difference between valsartan and placebo on the composite endpoint of CV death and HF hospitalization was significant [P = 0.0005; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.75-0.92)]. In patients with baseline renal impairment, the difference between the treatment groups was also significant (P = 0.0002; HR 0.76, 95% CI 0.66-0.88). Patients with EWRF had higher risk of CV death and HF hospitalization vs. those without ERWF (P < 0.0001; HR 1.44, 95% CI 1.21-1.71), and within the EWRF group a significant difference was also observed between valsartan and placebo (P = 0.0086; HR 0.63, 95% CI 0.45-0.89). However, the interaction between treatment and eGFR at Month 1 was not significant (P = 0.1160). Benefits were maintained in patients with renal dysfunction at baseline and those who experienced EWRF.

Renin inhibition ameliorates renal damage through prominent suppression of both angiotensin I and II in human renin angiotensinogen transgenic mice with high salt loading

The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of chronic kidney disease (CKD) progression. Aliskiren, a direct renin inhibitor, inhibits the rate-limiting step of the RAAS without any alternative pathway. It is proven to reduce albuminuria in CKD patients treated with angiotensin blockade. However, there are few reports which evaluate the advantage of aliskiren as the first-line drug against CKD progression in RAAS-activated hypertensive patients. Tsukuba hypertensive mice (THM), double transgenic mice carrying both the human renin and human angiotensinogen genes, were fed a high-salt diet and treated with hydraladine, ramipril and aliskiren for 10weeks. Blood pressure and urinary albumin excretion were measured every 2weeks during the experimental period. We evaluated renal histological changes and gene expression. Plasma angiotensin concentration was measured to evaluate the RAAS inhibitory effect. High-salt-loaded THM showed severe hypertension and renal injury. All antihypertensive drugs suppressed blood pressure and prevented renal disease progression. RAAS blockade showed a higher renoprotective effect than hydraladine despite an equivalent blood pressure lowering effect. Aliskiren exhibited even stronger renoprotection than ramipril. Plasma angiotensin concentration was increased in THM fed both normal salt and high salt. Hydraladine did not alter the plasma angiotensin concentration. Ramipril significantly decreased angiotensin II concentration. Aliskiren treatment almost completely suppressed angiotensin I and resulted in lower angiotensin II concentration than ramipril treatment. Aliskiren prevents renal disease progression by suppressing both angiotensin I and II in RAAS-activated pathology. Our data suggest the application of a renin inhibitor for preventing kidney disease progression in CKD patients.

The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes

Acute clamped hyperglycaemia activates the renin-angiotensin-aldosterone system (RAAS) and increases the urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Our objective was to determine whether blockade of the RAAS would blunt the effect of acute hyperglycaemia on urinary cytokine/chemokine excretion, thereby giving insights into potentially protective effects of these agents prior to the onset of clinical nephropathy. Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances) and urinary cytokines/chemokines were measured after 6 h of clamped euglycaemia (4-6 mmol/l) and hyperglycaemia (9-11 mmol/l) on two consecutive days in patients with type 1 diabetes mellitus (n = 27) without overt nephropathy. Measurements were repeated after treatment with aliskiren (300 mg daily) for 30 days. Before aliskiren, clamped hyperglycaemia increased filtration fraction (from 0.188 ± 0.007 to 0.206 ± 0.007, p = 0.003) and urinary fibroblast growth factor-2 (FGF2), IFN-α2 and macrophage-derived chemokine (MDC) (p < 0.005). After aliskiren, the filtration fraction response to hyperglycaemia was abolished, resulting in a lower filtration fraction after aliskiren under clamped hyperglycaemic conditions (p = 0.004), and none of the biomarkers increased in response to hyperglycaemia. Aliskiren therapy also reduced levels of urinary eotaxin, FGF2, IFN-α2, IL-2 and MDC during clamped hyperglycaemia (p < 0.005). The increased urinary excretion of inflammatory cytokines/chemokines in response to acute hyperglycaemia is blunted by RAAS blockade in humans with uncomplicated type 1 diabetes mellitus.

Optimal renin–angiotensin–aldosterone system blockade—wish fulfilled

Optimal renin–angiotensin–aldosterone system blockade—wish fulfilled

Myocardial extracellular volume fraction quantified by cardiovascular magnetic resonance is increased in diabetes and associated with mortality and incident heart failure admission

Diabetes may promote myocardial extracellular matrix (ECM) expansion that increases vulnerability. We hypothesized that: (i) type 2 diabetes would be associated with quantitative cardiovascular magnetic resonance (CMR) measures of myocardial ECM expansion, i.e. extracellular volume fraction (ECV); (ii) medications blocking the renin-angiotensin-aldosterone system (RAAS) would be associated with lower ECV; and (iii) ECV in diabetic individuals would be associated with mortality and/or incident hospitalization for heart failure. We enrolled 1176 consecutive patients referred for CMR without amyloidosis and computed ECV from measures of the haematocrit and myocardial and blood T1 pre- and post-contrast. Linear regression modelled ECV; Cox regression modelled mortality and/or hospitalization for heart failure. Diabetic individuals (n = 231) had higher median ECV than those without diabetes (n = 945): 30.2% (IQR: 26.9-32.7) vs. 28.1% (IQR: 25.9-31.0), respectively, P < 0.001). Diabetes remained associated with higher ECV in models adjusting for demographics, comorbidities, and medications (P < 0.001). Renin-angiotensin-aldosterone system blockade was associated with lower ECV (P = 0.028) in multivariable linear models. Over a median of 1.3 years (IQR: 0.8-1.9), 38 diabetic individuals had events (21 incident hospitalizations for heart failure; 24 deaths), and ECV was associated with these events (HR: 1.52, 95% CI: 1.21-1.89 per 3% ECV increase) in multivariable Cox regression models. Diabetes is associated with increased ECV. Extracellular volume fraction detects amelioration of ECM expansion associated with RAAS blockade, and is associated with mortality and/or incident hospitalization for heart failure in diabetic individuals. Extracellular matrix expansion may be an important intermediate phenotype in diabetic individuals that is detectable and treatable.

Optimal blockade of the renin–angiotensin–aldosterone system

Inhibition of the renin–angiotensin–aldosterone system (RAAS) is a successful therapy for hypertension, heart failure, and renal insufficiency. Overdosing of RAAS inhibitors is occasionally observed when several agents are used together, and can cause adverse events such as hypotension, hyperkalaemia, and renal failure. We advocate optimal, rather than complete, RAAS blockade.