aliskiren and Diabetic-Nephropathies

Aliskiren is a newly developed drug. Its role in lowering BP has been recognized. However, the role of aliskiren in treating heart and renal diseases are still controversial.. To evaluate the existing evidence about clinical efficacy, safety and tolerability of aliskiren monotherapy (AM).. An umbrella review of systematic reviews of interventional studies. We searched Pubmed, Embase and Cochrane Library up to June 2019. Two reviewers applied inclusion criteria to the select potential articles independently. The extract and analyze of accessible data were did by two reviewers independently too. Discrepancies were resolved with discussion or the arbitration of the third author.. Eventually, our review identified 14 eligible studies. Results showed that for essential hypertension patients, aliskiren showed a great superiority over placebo in BP reduction, BP response rate and BP control rate. Aliskiren and placebo, ARBs or ACEIs showed no difference in the number or extent of adverse events. For heart failure patients, AM did not reduce BNP levels (SMD -0.08, - 0.31 to 0.15) or mortality rate (RR 0.76, 0.32 to 1.80), but it decreased NT-proBNP (SMD -0.12, - 0.21 to - 0.03) and PRA levels (SMD 0.52, 0.30 to 0.75), increased PRC levels (SMD -0.66, - 0.8 to - 0.44). For patients who are suffered from hypertension and diabetes and/or nephropathy or albuminuria at the same time, aliskiren produced no significant effects (RR 0.97, 0.81 to 1.16).. We found solid evidence to support the benefits of aliskiren in the treatment of essential hypertension, aliskiren can produce significant effects in lowering BP and reliable safety. However, the effects of aliskiren in cardiovascular and renal outcomes were insignificant.. Study has been registered in PROSPERO (CRD42019142141).

Topics: Albuminuria; Amides; Antihypertensive Agents; Blood Pressure; Diabetic Nephropathies; Essential Hypertension; Fumarates; Heart Failure; Humans; Renin; Systematic Reviews as Topic; Treatment Outcome

Soon after the emergence of the renin-angiotensin-aldosterone system (RAAS) blocking treatment as the cornerstone of renoprotective treatment in the prevention and treatment of diabetic and nondiabetic CKD, it was investigated if a higher degree of achievable RAAS blockade by combining more than one compound is feasible and advantageous. Regardless of the benefits from using monotherapy for diabetic kidney disease, there is still much improvement to wish for in terms of kidney prognosis in these populations. A great deal of research has gone into evaluating combinations of the RAAS blocking treatments in different populations and with different drugs and doses. Studies have mostly been short-term and use surrogate endpoints such as albuminuria. Side effects have been well known and expected in terms of increasing potassium levels and hypotension, but to an acceptable extent. With recent disappointing results from major hard endpoint trials using dual RAAS blockade the concept is now under scrutiny. In this review we will discuss the pros and cons of dual RAAS blockade, with facts and findings from smaller studies, endpoint trials, and meta-analyses.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetic Nephropathies; Drug Therapy, Combination; Fumarates; Humans; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Risk Assessment; Treatment Outcome

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Renin-angiotensin-aldosterone system (RAAS) plays a critical role in the development of DKD with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) being the mainstay of treatment. Systemic RAAS activity has been implicated in the pathogenesis of DKD, but lately interest has shifted to intrarenal RAAS effect. With the discovery of the (pro)renin receptor and ACE independent pathways of angiotensin II production, our understanding of role of renin in end organ damage has improved significantly.. We summarize our current understanding of ACE dependent and independent pathways in the development of DKD and the preclinical models demonstrating renal effects of direct renin inhibitors (DRIs). We then review clinical studies and trials performed so far evaluating the efficacy of aliskiren on renal outcomes and safety in DKD.. At present, there is little evidence for renal benefit of aliskiren in DKD beyond that offered by ACEIs or ARBs. Combining aliskiren with ACEI or ARB in DKD did not significantly improve renal outcomes in comparison with ACEI or ARB monotherapy in clinical trials. Slightly more adverse events including hyperkalemia, acute kidney injury and hypotension were observed in the combination therapy as compared to the monotherapy. Thus, current evidence suggests that aliskiren, because of its antihypertensive and antiproteinuric effects, maybe used as monotherapy in DKD and considered an equivalent alternative to ACEIs or ARBs. Careful monitoring for renal adverse effects would allow safe clinical use of DRI.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Fumarates; Humans; Renin; Renin-Angiotensin System

For approximately 6 years, the only commercially available direct renin inhibitor, aliskiren, which inhibits the renin-angiotensin-aldosterone system at the initial rate limiting step, has been marketed for the treatment of hypertension. Concurrently, much attention has been given to the possibility that renin inhibition could hold potential for improved treatment in patients with chronic kidney disease, with diabetic nephropathy as an obvious group of patients to investigate, as the activity of the renin-angiotensin-aldosterone system is enhanced in these patients and as there is an unmet need for improved treatment and prognosis in these patients. Several short term studies have been performed in diabetic nephropathy, showing a consistent effect on the surrogate endpoint lowering of albuminuria, both as monotherapy and in combination with other blockers of the renin-angiotensin-aldosterone system. In addition, combination treatment also seemed safe and effective in patients with impaired kidney function. These initial findings formed the basis for the design of a large morbidity and mortality trial investigating aliskiren as add-on to standard treatment. The study has just concluded, but was terminated early as a beneficial effect was unlikely and there was an increased frequency of side effects. Also in non-diabetic kidney disease a few intervention studies have been carried out, but there is no ongoing hard outcome study. In this review we provide the current evidence for renin inhibition in chronic kidney disease by reporting the studies published so far as well as a perspective on the future possibilities.

Topics: Amides; Angiotensin Receptor Antagonists; Animals; Clinical Trials as Topic; Diabetic Nephropathies; Drug Therapy, Combination; Fumarates; Humans; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Treatment Outcome

Inhibition of the RAAS (renin-angiotensin-aldosterone system) plays a pivotal role in the prevention and treatment of diabetic nephropathy and a spectrum of other proteinuric kidney diseases. Despite documented beneficial effects of RAAS inhibitors in diabetic patients with nephropathy, reversal of the progressive course of this disorder or at least long-term stabilization of renal function are often difficult to achieve, and many patients still progress to end-stage renal disease. Incomplete inhibition of the RAAS has been postulated as one of reasons for unsatisfactory therapeutic responses to RAAS inhibition in some patients. Inhibition of renin, a rate-limiting step in the RAAS activation cascade, could overcome at least some of the abovementioned problems associated with the treatment with traditional RAAS inhibitors. The present review focuses on experimental and clinical studies evaluating the two principal approaches to renin inhibition, namely direct renin inhibition with aliskiren and inhibition of the (pro)renin receptor. Moreover, the possibilities of renin inhibition and nephroprotection by interventions primarily aiming at non-RAAS targets, such as vitamin D, urocortins or inhibition of the succinate receptor GPR91 and cyclo-oxygenase-2, are also discussed.

Topics: Amides; Animals; Cyclooxygenase 2 Inhibitors; Diabetic Nephropathies; Fumarates; Humans; Kidney Failure, Chronic; Prorenin Receptor; Receptors, Calcitriol; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Renin; Renin-Angiotensin System; Urocortins; Vitamin D

Topics: Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Calcium Channel Agonists; Catheter Ablation; Cerebrovascular Circulation; Chronic Disease; Diabetic Nephropathies; Drug Therapy, Combination; Evidence-Based Medicine; Fumarates; Humans; Hypertension; Imidazoles; Kidney; Kidney Diseases; Randomized Controlled Trials as Topic; Tetrazoles; Valine; Valsartan

In the current context of renin-angiotensin-aldosterone system (RAAS) blockade, angiotensin (Ang) converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), or their combination, have proved to be effective in providing cardiovascular and renal protection. However, renin inhibition has long been recognized as the preferred site for blockade of the RAAS because renin represents the first, highly-regulated and rate-limiting step of the system. Up to now, the first orally active renin inhibitors initially tested in humans did not meet the necessary all the criteria (specificity, potency, and pharmacokinetic profile) to become clinically useful drugs. The synthesis of aliskiren, a potent alkane carboxamide renin inhibitor, now provides an orally active compound which, according to its pharmacological profile in normotensive subjects and in patients with hypertension, diabetic nephropathy or heart failure suggests that this drug may be of value for the treatment of patients with cardiovascular and renal disorders. However, long-term studies are needed to demonstrate the efficacy of aliskiren in these clinical settings. The results of the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Disease Endpoints (ALTITUDE) trial which has already included 8600 patients with type 2 diabetes, proteinuria and a high cardiovascular risk and compared the effects of aliskiren vs. a placebo on a composite endpoint including renal and cardiovascular morbidity and mortality should be provided in 2012.

Topics: Amides; Animals; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fumarates; Heart Failure; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System

The renin-angiotensin system (RAS) is the most important mechanism leading to cardiovascular and renal damage in diabetic patients. Studies conducted until now have unequivocally demonstrated that antihypertensive treatment with RAS blockers (angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers) improve the prognosis of patients with diabetes, by reducing rates of cardiovascular events and preventing or delaying the progression of diabetic nephropathy. However, despite the benefits of such treatment, cardio-renal events are still very frequent in diabetics. Several strategies for reducing this cardiovascular and renal risk have been proposed, but among them, a more complete blockade of the RAS seems the most attractive. Direct renin inhibitors are RAS blockers with some particularities, such as their ability to reduce plasma renin activity or the possibility to modulate tissue and intracellular RAS, which could represent a theoretical advantage when treating diabetic patients. In experimental and clinical studies conducted until now, aliskiren is able to reduce blood pressure in diabetics, alone or in combination with ACE inhibitors or angiotensin-receptor blockers. Moreover, aliskiren reduces markers of cardiac and renal disease, such as left ventricular hypertrophy or post-infarction ventricular remodeling, as well as proteinuria in diabetics already treated with other RAS blockers. The translation of these promising results to the clinical arena is currently being investigated in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), where more than 8600 diabetic patients with chronic kidney disease and at high-risk of cardio-renal events are treated with aliskiren or placebo added to the current treatment consisting of another RAS blocker. If positive, aliskiren will be the treatment of choice in the prevention of cardiorenal disease in diabetics.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Diabetes Complications; Diabetic Nephropathies; Fumarates; Humans; Hypertension; Renin

Direct renin inhibition is a new means for blocking the renin-angiotensin system at the rate-limiting step of the cascade of events triggered by renin release--the interaction of renin with its physiological substrate angiotensinogen. The remarkable success of angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers in the management of cardiovascular and renal disease has led to great interest in the potential of direct renin inhibitors. This Review focuses on the evidence that suggests that direct renin inhibitors might block the renin-angiotensin system in the kidney more completely than either angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers. The therapeutic implications of this evidence are also reviewed, as well as the possible mechanistic routes by which direct renin inhibition might exert its influence on the kidney.

Topics: Amides; Animals; Antihypertensive Agents; Diabetic Nephropathies; Fumarates; Humans; Hypertension, Renal; Renin; Renin-Angiotensin System

Diabetic nephropathy is the most common and most rapidly growing cause of end-stage renal failure in developed countries. Diabetic nephropathy results from complex interactions between genetic, metabolic and hemodynamic factors. Improvements in our understanding of the pathogenesis of fibrosis associated with diabetic kidney disease have led to the identification of several novel targets for the treatment of diabetic nephropathy. Albuminuria is a useful clinical marker of diabetic nephropathy, as it can be used to predict a decline in renal function. A reduction in albuminuria might not, however, be reflective of a protective effect of therapies focused on ameliorating renal fibrosis. Although new strategies for slowing down the progression of several types of renal disease have emerged, the challenge of arresting the relentless progression of diabetic nephropathy remains. In this Review, we discuss novel pharmacological approaches that aim to improve the renal outcomes of diabetic nephropathy, including the use of direct renin inhibitors and statins. We also discuss the promise of using antifibrotic agents to treat diabetic nephropathy. The need for novel biomarkers of diabetic nephropathy is also highlighted.

Topics: Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Biomarkers; Clinical Trials as Topic; Diabetic Nephropathies; Disease Progression; Fumarates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Protein Kinase C; Pyridones; Renin; Transforming Growth Factor beta

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Evidence-Based Medicine; Fumarates; Humans; Hypertension; Proteinuria; Treatment Outcome

Diabetes mellitus is an independent risk factor for cardiovascular disease (CVD) and current opinion holds that hyperglycemia directly damages smaller blood vessels, resulting in microvascular complications of nephropathy, retinopathy, and neuropathy. In a patient with diabetes, hypertension compounds and greatly increases the risk of microvascular complications, and thus the risk of end-stage kidney disease, vision loss, and nontraumatic limb amputations. Hypertension and hyperglycemia directly damage the microvasculature, leading to small vessel dysfunction that manifests as the clinical disease states of diabetic retinopathy and nephropathy. Early recognition and treatment of both hyperglycemia and hypertension may prevent vision loss and chronic kidney disease, the devastating outcomes of these microvascular complications. One of the pathogenic mechanisms for microvascular dysfunction is upregulation of the angiotensin II type 1 receptor, the most physiologically common receptor for the vasoconstrictor properties of angiotensin II. In patients with diabetic retinopathy and nephropathy, tight control of blood pressure (BP) (< 130/80 mm Hg) delays the progression of retinopathy and nephropathy in addition to reducing cardiovascular morbidity and mortality. Aggressive treatment with 2 or more antihypertensive agents, selected from different drug classes, is often needed to reach the optimal BP target level. A PubMed search was conducted to identify randomized controlled trials that evaluated hypertension control and microvascular outcomes in patients with diabetes. Several clinical trials have yielded promising data with renin-angiotensin-aldosterone system (RAAS) inhibitors (the direct renin inhibitor aliskiren, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers). Attainment of BP control with RAAS inhibitors reduces the risk for CVD, nephropathy, and retinopathy. In addition, RAAS inhibitors have demonstrated renoprotective effectiveness independent of the BP reduction achieved. This review will examine the results of clinical trials in the context of BP control, diabetes, and the microvascular complications of retinopathy and nephropathy.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetes Mellitus; Diabetic Nephropathies; Diabetic Retinopathy; Disease Progression; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Microvessels

Current therapies proven to slow the progression of diabetic nephropathy include blockade of the renin-angiotensin system (RAS) with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Given our better understanding of the pathophysiology of diabetic nephropathy, newer therapies to treat this condition are slowly emerging.. Animal studies and a single clinical trial demonstrate efficacy of the renin inhibitor, aliskiren, to decrease a marker of nephropathy progression, that is albuminuria. On the basis of animal study results, pyridoxamine, an inhibitor of advanced glycation and ruboxistaurin, a protein kinase C inhibitor showed promise as new agent to treat nephropathy. The clinical trial results were less than gratifying, however. Sulodexide, a glycosaminoglycan, works to reduce proteinuria presumably by restoring the already reduced glycoproteins present in the glomerular basement membrane. Like other agents, sulodexide also looked promising in animal studies, but failed to demonstrate albuminuria reduction in a large multicentre clinical trial (SUN-Micro-Trial).. This review summarizes newer therapies for slowing the progression of diabetic nephropathy. Aliskiren shows promise from small clinical studies, but we await the results of the multicentre, international ALTITUDE trial in about 2012. On the basis of the results of trials only, pyridoxamine may have a chance at further evaluation, but that is also unclear.

Topics: Amides; Animals; Diabetic Nephropathies; Fumarates; Humans; Indoles; Maleimides; Pyridoxamine; Superoxides

Arterial hypertension is an independent risk factor for cardiovascular diseases and one of the major causes for mortality worldwide. Drugs, that control hypertension effectively are therefore needed to reduce hypertension induced morbidity and mortality. The inhibition of the renin-angiotensin-aldosterone-system (RAAS) is one target to control blood pressure in these patients. The new direct renin inhibitor aliskiren is one new substance on the market to inhibit the RAAS effectively by suppression of the plasma renin activity, which inhibits the RAAS at its rate-limiting step. Therefore, aliskiren in monotherapy and in combination might yield beneficial effects for the patients. Nevertheless, blood pressure lowering has to be combined with a reduction of target organ damage for all drug classes prescribed to patients with hypertension. Therefore, we review here the major effects of this new drug not only in regard to hypertension but also in regard to target organ damage reduction and possible changes in morbidity and mortality, which future trials will investigate.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Biphenyl Compounds; Cardiovascular Diseases; Diabetic Nephropathies; Diuretics; Drug Therapy, Combination; Europe; Fumarates; Germany; Heart Failure; Humans; Hydrochlorothiazide; Hypertension; Irbesartan; Japan; Prevalence; Prorenin Receptor; Protein Precursors; Randomized Controlled Trials as Topic; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Risk Factors; Tetrazoles; Time Factors; World Health Organization

The importance of renin-angiotensin aldosterone system (RAAS) in cardiovascular and renal diseases has long ago been recognized. However despite the availability of many effective drugs, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, RAAS blockade is incomplete in several patients with consequent uncontrolled high blood pressure and not efficacy cardiovascular and renal protection. Aliskiren is a new renin inhibitor that block the RAAS at its origin. Recent studies suggest that Aliskiren reduces blood pressure, inhibits plasma renin activity and attenuates renal damage in diabetic patients with nephropathy. This review summarized the results of the more important studies performed in hypertensive and diabetic patients in which Aliskiren showed to be a safe and effective antihypertensive agent that can be used in monotherapy or in combination with other drugs to provide additional options to improve blood pressure control.

Topics: Aldosterone; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Clinical Trials as Topic; Diabetic Nephropathies; Double-Blind Method; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System

Sodium retention and volume overload are the main determinants of poor response to renin-angiotensin-aldosterone system (RAAS) inhibition in patients with diabetes. As volume excess can exist without symptoms, biomarkers are needed to identify a priori which patients are volume overloaded and may experience less benefit from RAAS inhibition. N-terminal pro-brain natriuretic peptide (NT-proBNP) is released in the setting of increased cardiac wall stress and volume overload. We conducted a post hoc analysis among 5081 patients with type 2 diabetes mellitus participating in the ALTITUDE trial to investigate whether NTproBNP can predict the effects of additional therapy with aliskiren on cardio-renal endpoints. Aliskiren compared to placebo reduced the risk of the primary cardio-renal endpoint events by 20% (95% confidence interval [CI] 16 to 61) and 2% (95% CI -42 to 30) in the two lowest NT-proBNP tertiles, and it increased the risk by 25% (95% CI -4 to 96) in the highest NT-proBNP tertile (P value for trend = 0.009). Similar trends were observed for the cardiovascular and end-stage renal disease endpoints. Effects of aliskiren compared to placebo on safety outcomes (hyperkalaemia and hospitalization for acute kidney injury) were independent of NT-proBNP. In conclusion, baseline NT-proBNP may be used as a marker to predict the response to aliskiren with regard to cardio-renal outcomes when added to standard therapy with RAAS inhibition.

Topics: Aged; Amides; Antihypertensive Agents; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypoglycemic Agents; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Renin-Angiotensin System; Risk Factors; Treatment Outcome

In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity.. We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to <30 mg/g of albumin-to-creatinine ratio) or microalbuminuria (30 to <300 mg/g) to the DRI group or ARB group (any ARB) with a target blood pressure of <130/80 mmHg. The primary endpoint was a reduction in albuminuria.. Twelve patients dropped out during the observation period, and a total of 225 patients were analyzed. During the study period, the systolic and diastolic blood pressures were not different between the groups. The changes in the urinary albumin-to-creatinine ratio from baseline to the end of the treatment period in the DRI and ARB groups were similar (-5.5% and -6.7%, respectively). In contrast, a significant reduction in the urinary excretion of angiotensinogen was observed in the ARB group but not in the DRI group. In the subgroup analysis, a significant reduction in the albuminuria was observed in the ARB group but not in the DRI group among high-normal albuminuria patients.. DRI and ARB reduced albuminuria in hypertensive patients with type 2 diabetes. In addition, ARB, but not DRI, reduced albuminuria even in patients with normal albuminuria. DRI is not superior to ARB in the reduction of urinary excretion of albumin and angiotensinogen.

Topics: Albuminuria; Amides; Angiotensin Receptor Antagonists; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Prospective Studies; Renin; Renin-Angiotensin System; Treatment Outcome

We aimed to assess the effect of aliskiren treatment on blood pressure, albuminuria, and kidney function in patients with chronic kidney disease (CKD). We conducted a prospective, open-label study of 67 patients with CKD who were already being treated with other antihypertensives. Inclusion criteria were blood pressure (BP) ≥130/80 mmHg, albuminuria ≥30 mg/g, and estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m(2). Subjects were treated with 150 mg/day aliskiren, which was increased to 300 mg/day for the 24-week study period. Aliskiren effectively reduced both systolic and diastolic BP, plasma renin activity (PRA), serum aldosterone concentration, albuminuria, urinary N-acetyl-glucosaminidase, and urinary β2-microglobulin levels. Although eGFR was significantly decreased after 4 weeks of aliskiren treatment, it recovered to a pretreatment level within 12 weeks of treatment initiation. There were no significant differences in the percent reduction of albuminuria or changes of eGFR levels when the subjects were divided into three groups on the basis of baseline eGFR (stages 1/2, 3, and 4) and the presence or absence of diabetes mellitus (DM group and non-DM group). Furthermore, in patients not treated with renin-angiotensin-aldosterone-system (RAAS) inhibitors, including angiotensin receptor blockers or angiotensin-converting enzyme inhibitors at baseline, changes in eGFR were significantly increased compared with those already treated with RAAS inhibitors at baseline. Aliskiren administration reduced BP, PRA, serum aldosterone levels, and albuminuria, while maintaining eGFR, regardless of the presence or absence of DM or the degree of eGFR.

Topics: Aged; Albuminuria; Aldosterone; Amides; Antihypertensive Agents; Biomarkers; Blood Pressure; Diabetic Nephropathies; Drug Therapy, Combination; Female; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Japan; Kidney; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Time Factors; Treatment Outcome

Aldosterone blockade reduces albuminuria in diabetic patients with chronic kidney disease (CKD), and improves prognosis in chronic heart failure. This study assessed the effects of direct renin inhibition with aliskiren in combination with losartan and optimal antihypertensive therapy on urinary aldosterone, plasma renin activity (PRA) and plasma renin concentration (PRC).. In the AVOID study, 599 patients with type 2 diabetes, hypertension and nephropathy received 6 months aliskiren (150 mg force titrated to 300 mg once daily after 3 months) or placebo added to losartan 100 mg and optimal antihypertensive therapy. Urinary aldosterone excretion, PRA and PRC were measured at baseline and after 24 weeks in a prespecified subset of 133 patients.. Aliskiren added to losartan provided reductions from baseline in urinary aldosterone compared with adding placebo (-24% vs. -4%, p = 0.017) at week 24. There was no significant difference between the aliskiren and placebo groups in the proportion of patients with aldosterone breakthrough (aliskiren 35%, placebo 46%, p = 0.199). Aliskiren treatment reduced PRA by 90% at 24 weeks and increased PRC by 328%.. Adding aliskiren to recommended renoprotective treatment with losartan and optimal antihypertensive therapy provided significant reductions in urinary aldosterone excretion which may attenuate decline in kidney function.

Topics: Aldosterone; Amides; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Fumarates; Humans; Male; Middle Aged; Renin

Topics: Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Carotid Intima-Media Thickness; Diabetic Nephropathies; Drug Therapy, Combination; Female; Fumarates; Humans; Kidney Tubules; Male; Middle Aged

This open-label, randomized, parallel-controlled study investigated the effects of the direct renin inhibitor aliskiren on 64 hypertensive type 2 diabetic patients with chronic kidney disease (CKD) and stable glycemic control who were already being treated with fixed doses of antihypertensive agents over a 24-week period. These agents were 80 mg of the angiotensin II receptor blocker (ARB) telmisartan and 5 mg of the calcium channel blocker (CCB) amlodipine. Patients were randomly assigned to two groups: the aliskiren group, receiving 150 mg per day aliskiren, which was increased to 300 mg per day (n=32), and the CCB group, which received an increased dose (7.5 mg per day) of amlodipine that was increased to 10 mg per day (n=32). Urinary albumin excretion and urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and liver-type fatty acid-binding protein (L-FABP) were investigated in each group. Mean systolic and diastolic blood pressure decreased significantly in both groups, but there was no significant difference between the two groups at the end of the study. Serum creatinine levels and estimated glomerular filtration rate did not differ significantly between the two groups, but percent changes of urinary albumin/creatinine ratios, 8-OHdG and L-FABP levels decreased significantly in the aliskiren group compared with the CCB group. Plasma aldosterone levels were significantly decreased in the aliskiren group, which correlated significantly with those of urinary 8-OHdG and L-FABP. Our results suggest that the addition of aliskiren to the maximal recommended dose of ARB and usual dose of amlodipine is more effective in reducing albuminuria and oxidant stress in hypertensive diabetic patients with CKD than increasing the dose of amlodipine.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Albuminuria; Aldosterone; Amides; Amlodipine; Angiotensin II Type 2 Receptor Blockers; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Calcium Channel Blockers; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Fatty Acid-Binding Proteins; Female; Fumarates; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Male; Middle Aged; Renin; Telmisartan; Young Adult

Elevated BP contributes to development and progression of proteinuria and decline in renal function in patients with type 2 diabetes. Our post hoc analysis assessed the baseline BP influence on the antiproteinuric effect in the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study.. In the AVOID study, 599 hypertensive type 2 diabetic patients with nephropathy received 6 months of aliskiren (150 mg force titrated to 300 mg daily after 3 months) or placebo added to losartan (100 mg) daily and optimal antihypertensive therapy. Changes in early morning urinary albumin:creatinine ratio and eGFR at week 24 were assessed by subgroups of baseline BP: Group A (prespecified target), <130/80 mmHg (n=159); Group B, <140/90 mmHg but ≥130/80 mmHg (n=189); and Group C (insufficient BP control), ≥140/90 mmHg (n=251).. Mean baseline BP (mmHg) levels for Groups A, B, and C were 120/71, 133/78, and 145/81, respectively. BP during the trial was nearly identical to baseline levels in all groups. The antiproteinuric effects of aliskiren were consistent across subgroups of baseline BP (19 to 22% reduction versus placebo). In Group C, the decline in eGFR was significantly lower with aliskiren than with placebo (P=0.013).. Aliskiren (300 mg) added to losartan (100 mg) plus optimal antihypertensive therapy provides antiproteinuric effects independent of BP in patients with type 2 diabetes and nephropathy. Renal function was better preserved with aliskiren in patients with insufficient BP control.

Topics: Aged; Albuminuria; Amides; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension, Renal; Losartan; Male; Middle Aged; Placebos; Treatment Outcome

Proteinuric diabetic patients with reduced glomerular filtration rate (GFR) are at high risk of renal and cardiovascular disease progression and treatment-related adverse events. This post hoc analysis assessed the efficacy and safety of aliskiren added to the maximal recommended dose of losartan according to baseline estimated GFR (eGFR) (stage 1-3 chronic kidney disease [CKD]).. In the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study, 599 hypertensive patients with type 2 diabetes and nephropathy received 6 months of aliskiren (150 mg daily titrated to 300 mg daily after 3 months) or placebo added to 100 mg losartan and optimal antihypertensive therapy. Exclusion criteria included eGFR<30 ml/min per 1.73 m2 and serum potassium>5.1 mmol/l.. Baseline characteristics were similar between treatment groups in all CKD stages. The antiproteinuric effects of aliskiren were consistent across CKD stages (19, 22, and 18% reduction). In the stage 3 CKD group, baseline serum creatinine levels were equal, but renal dysfunction, prespecified as a postrandomization serum creatinine elevation>176.8 μmol/l (2.0 mg/dl) occurred more frequently in the placebo group (29.2 vs. 13.6%, P=0.032). Serum potassium elevations>5.5 mmol/l (based on a single measurement) were more frequent with aliskiren (22.5 vs. 13.6%) in stage 3 CKD. Adverse event rates were similar between treatments, irrespective of CKD stage.. Aliskiren added to losartan reduced albuminuria and renal dysfunction and was well tolerated, except for hyperkalemia (stage 3), independent of baseline CKD stage in patients with type 2 diabetes, hypertension, and nephropathy.

Topics: Aged; Albuminuria; Amides; Antihypertensive Agents; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Fumarates; Humans; Kidney Diseases; Kidney Function Tests; Losartan; Male; Middle Aged

Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy.. We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months.. The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups.. Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955 [ClinicalTrials.gov].).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Losartan; Male; Middle Aged; Multivariate Analysis; Proteinuria; Renin

Considering the importance of the renin-angiotensin system (RAS) in diabetic nephropathy (DN) and the link between mast cells (MC) and the RAS, this study evaluated the effects of RAS blockade on the MC cell population in the kidneys from rats with experimental diabetes. Wistar rats were divided into six groups: control non-diabetic (C); sham (S); diabetic (D); and D treated with enalapril (EN), losartan (LO), or aliskiren (AL). Ninety days after diabetes induction, glomerular filtration rate (GFR) and urinary albumin excretion (UAE) were determined. Kidneys were collected for MC counting. RAS blockers minimized changes in morphometrical parameters (EN), cortical collagen (LO, AL), GFR (AL) and UAE (EN, LO). An increased number of MC was observed in the kidneys from D animals. Only AL treatment prevented this increase. MC may be involved in some aspects of DN pathogenesis and the possible protective effects of AL on the kidneys might involve MC modulation.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Fumarates; Glomerular Filtration Rate; Losartan; Male; Mast Cells; Rats; Rats, Wistar; Renin-Angiotensin System

Objective To investigate the role of aliskiren (AL) in the angiotensinII/ angiotensin 1-7 (AngII/Ang1-7) signal pathway in renal tissue of diabetic nephropathy (DN) rats. Methods 40 male SD rats were randomly divided into 4 groups including normal group, diabetes group, AL group and valsartan (Val) group. Animal models of diabetes were induced by high fat diet combined with small dose of streptozotocin injection. Rats in AL group were administered 50 mg/(kg.d) AL by gavage, and rats in Val group were administered 30 mg/(kg.d)Val by gavage. 24-hour urine protein (24 h-UP) were observed by Coomassie blue colorimetry at 2, 4 and 6 weeks after modeling, serum creatinine was detected by automatic biochemical analyser, kidney index [kidneys mass(g)/body mass (kg)] was measured. HE and PAS staining were used to observe renal pathological changes. Immunohistochemistry was used to detect the expression of ACE2, MAS receptor, AT1R and AT2R in the kidney. Results After 6 weeks of modeling, there was no significant difference in creatinine level among groups. The levels of glucose, 24 h-UP and kidney index in diabetes group, AL group and Val group significantly increased. Compared with diabetes group, the levels of 24 h-UP and kidney index were lower in AL group and Val group. Immunohistochemistry showed that the expression of AT2R and ACE2 was lower and the expression of MAS receptor was higher in AL group than diabetes group and Val group. Compared to normal group and Val group, AT1R expression was significantly up-regulated in AL group, without significant difference between diabetes group and AL group. Conclusion AL down-regulates the expression of AT2R and ACE2, thus inhibits the AngII/ Ang1-7 signal axis and improves/alleviates the symptoms in diabetic rats.

Topics: Amides; Angiotensin I; Angiotensin II; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fumarates; Male; Peptide Fragments; Random Allocation; Rats; Rats, Sprague-Dawley; Signal Transduction

Since chronic kidney disease due to diabetic nephropathy (DN) is becoming an ever larger health burden worldwide, more effective therapies are desperately needed. In the present study, the anti-diabetic and renoprotective effects of aliskiren have been evaluated in streptozotocin (STZ)-induced DN in rats. DN was induced by a single intraperitoneal injection of STZ (65 mg/kg). Three weeks after STZ, rats were divided into four groups; normal, diabetic, diabetic treated with gliclazide (10 mg/kg/day) for 1 month, and diabetic treated with aliskiren (50 mg/kg/day) for 1 month. At the end of the experiment, mean arterial blood pressure and heart rate were recorded. Rats were then euthanized and serum was separated for determination of glucose, insulin, kidney function tests, superoxide dismutase activity (SOD), adiponectin, and tumor necrosis factor-alpha (TNF-α). One kidney was used for estimation of malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) contents. Other kidney was used for histopathological study and immunohistochemical measurement of caspase-3 and transforming growth factor beta (TGF-β). In addition, islets of Langerhans were isolated from normal rats by collagenase digestion technique for in vitro study. Aliskiren normalized STZ-induced hyperglycemia, increased insulin level both in vivo and in vitro, normalized kidney function tests and blood pressure, and alleviated STZ-induced kidney histopathological changes. This could be related to the ability of aliskiren toward preserving hemodynamic changes and alleviating oxidative stress and inflammatory and apoptotic markers induced by STZ in rats. However, aliskiren was more effective than gliclazide in relieving STZ-induced DN. These findings support the beneficial effect of aliskiren treatment in DN which could be attributed to its anti-diabetic, renoprotective, antioxidant, anti-inflammatory, and anti-apoptotic effects. Moreover, clinical studies are required to establish the effectiveness of aliskiren treatment in patients suffering from hypertension and diabetes.

Topics: Amides; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers; Blood Glucose; Blood Pressure; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Fumarates; Gliclazide; Heart Rate; Hypoglycemic Agents; Inflammation Mediators; Insulin; Insulin-Secreting Cells; Kidney; Oxidative Stress; Rats, Wistar; Streptozocin; Urological Agents

Albuminuria change is often used to assess drug efficacy in intervention trials in nephrology. The change is often calculated using a variable number of urine samples collected at baseline and end of treatment. Yet more albuminuria measurements usually occur. Because albuminuria shows a large day-to-day variability, this study assessed to what extent the average and the precision of the antialbuminuric drug effect varies with the number of urine collections at each visit and the number of follow-up visits.. This study used data from three randomized intervention trials (Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy, Selective Vitamin D Receptor Activation for Albuminuria Lowering, and Residual Albuminuria Lowering with Endothelin Antagonist Atrasentan) including patients with type 2 diabetes and macroalbuminuria. Albuminuria-lowering drug effects were estimated from one, two, or three urine collections at consecutive days before each study visit and reported as albuminuria change from baseline to end of treatment or the change over time considering an average of all follow-up albuminuria measurements.. Increasing the number of urine collections for an albuminuria measurement at baseline and end of treatment or using all study visits during follow-up did not alter the average drug effect. The precision of the drug effect increased (decreased SEM) when the number of study visits and the number of urine collections per visit were increased. Using all albuminuria measurements at all study visits led to a 4- to 6-fold reduction in sample size to detect a 30% albuminuria-lowering treatment effect with 80% power compared with using baseline and end-of-treatment albuminuria measurements alone.. Increasing the number of urine collections per study visit and the number of visits over time does not change the average drug effect estimate but markedly increases the precision, thereby enhancing statistical power. Thus, clinical trial designs in diabetic nephropathy using albuminuria as an end point can be significantly improved, leading to smaller sample sizes and less complex trials.

Topics: Aged; Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Atrasentan; Bone Density Conservation Agents; Diabetic Nephropathies; Endothelin Receptor Antagonists; Ergocalciferols; Female; Fumarates; Humans; Losartan; Male; Middle Aged; Office Visits; Pyrrolidines; Randomized Controlled Trials as Topic; Research Design; Statistics as Topic; Urine Specimen Collection

We recently developed and validated in existing trials a novel algorithm (PRE score) to predict long-term drug efficacy based on short-term (month-6) drug-induced changes in multiple risk markers. To show the value of the PRE score for ongoing and planned clinical trials, we here report the predicted long-term cardio-renal efficacy of aliskiren in type 2 diabetes, which was investigated in the ALTITUDE trial, but unknown at the time this study was conducted.. We established the relation between multiple risk markers and cardio-renal endpoints (as defined in ALTITUDE) using a background database from past clinical trials. The short-term effect of aliskiren on multiple risk markers was taken from the AVOID trial. A PRE score was developed by multivariate Cox analysis in the background population and was then applied to the baseline and month-6 measurements of the aliskiren treatment arm of the AVOID trial to predict cardio-renal risk. The net risk difference at these time-points, after correction for placebo effects, was taken to indicate the estimated long-term cardio-renal risk change.. Based on the PRE score, we predicted that aliskiren treatment in ALTITUDE would confer a relative risk change of -7.9% (95% CI -2.5 to -13.4) for the cardio-renal endpoint, a risk change of -5.1% (-1.2 to -9.0) for the CV endpoint and a non-significant risk change of -19.9% (-42.1 to +2.1) for the renal endpoint.. PRE score estimations suggested that aliskiren has only a marginal additive protective effect on cardio-renal endpoints. These predictions were validated by the results of the ALTITUDE trial, confirming the potential of the PRE score to prospectively predict drug efficacy on cardio-renal outcomes.

Topics: Aged; Algorithms; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Cardiovascular Diseases; Decision Support Techniques; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Female; Fumarates; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Renin-Angiotensin System; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

We investigated whether aliskiren, a direct renin inhibitor, provided protection in a model of diabetic nephropathy in mice and compared its protective effects to valsartan, an angiotensin II type 1 receptor blocker.. Hyperglycemia was induced with streptozotocin (STZ, 40 mg/kg/day × 5 days) injection in DBA/2J mice fed on a high fat diet. Mice were treated with either aliskiren (25 mg/kg/day) or valsartan (8 mg/kg/day) for 6 weeks.. Aliskiren and/or valsartan treatment significantly attenuated albuminuria, urinary nephrin excretion and glomerulosclerosis. Aliskiren and/or valsartan prevented reduction of podocin and WT1 protein abundance in diabetic mice. Aliskiren and/or valsartan significantly prevented increased expression of profibrotic growth factors (TGFβ, CTGF and PAI-1), proinflammatory cytokines (MCP-1, TNFα and IL-1β), endoplasmic reticulum (ER) stress markers (CHOP and XBP-1) and lipid accumulation in the kidney of diabetic animals. Aliskiren showed similar efficacy compared to valsartan therapy and dual treatment in some aspects has synergistic protective effects.. Our study indicates that aliskiren and/or valsartan protects against diabetic kidney disease through multiple mechanisms, including decreasing podocyte injury, activation of profibrotic growth factors and proinflammatory cytokines, ER stress and accumulation of lipids.

Topics: Albumins; Amides; Animals; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endoplasmic Reticulum Stress; Fumarates; Inflammation; Lipid Metabolism; Male; Membrane Proteins; Mesangial Cells; Mice, Inbred DBA; Podocytes; Protective Agents; Proteinuria; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

The aim of the present study was to investigate the effect of combination of aliskiren with paricalcitol on experimental diabetic nephropathy (DN) model in rats.. Forty male Sprague Dawley rats were divided into 5 groups of 8 rats each, namely the control (Group C), diabetes (Group D), aliskiren (Group A), paricalcitol (Group P), and aliskiren plus paricalcitol (Group A+P) groups. Aliskiren was given by oral-gavage at a dose of 50 mg/kg/day once daily for 12 weeks. Paricalcitol was given by intraperitoneally at a dose of 0,4 µg/kg/three day of week for 12 weeks. Renal function parameters, oxidative stress biomarkers, mRNA expression of renin-angiotensin system parameters and kidney histology were determined.. Group A+P had lower mean albümin-to-creatinine ratio (ACR) (p=0.004) as well as higher creatinine clearance (CCr) (p<0.005) than the diabetic rats (Group D). Combination therapy significantly increased CCr (Group A+P vs. Group A, p<0.005; Group A+P vs. Group P, p=0.022) and reduced ACR (Group A+P vs. Group A, p=0.018; Group A+P vs. Group P, p<0.005) when compared to monotherapy. Serum malondialdehyde levels were significantly lower (p=0.004); glutathion levels (p=0.003), glutathion peroxidase (p=0.004) and superoxide dismutase (p<0.005) activities were significantly higher in group A+P than in group D. The mean scores of mRNA expression of renin (p<0.005), angiotensin II (p=0.012) and angiotensin type 1 receptor (p=0.018) in group A+P were significantly lower. Although combination therapy showed no additional effect on oxidative system, renin-angiotensin system and renal histology, aliskiren plus paricalcitol significantly decreased interstitial fibrosis volume when compared to monotherapy (Group A+P vs. Group A, p<0.005; Group A+P vs. Group P, p=0.002).. Our data seem to suggest a potential role of aliskiren plus paricalcitol acting synergystically for reducing the progression of diabetic nephropathy in an experimental rat model.

Topics: Amides; Animals; Antihypertensive Agents; Antioxidants; Biomarkers; Bone Density Conservation Agents; Diabetic Nephropathies; Disease Progression; Drug Therapy, Combination; Ergocalciferols; Fumarates; Kidney; Kidney Function Tests; Lipid Peroxidation; Male; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

Our previous study indicated that the exchange from an angiotensin receptor blocker (ARB) to aliskiren reduced morning blood pressure and albuminuria in hypertensive patients with diabetic nephropathy. We extended the above study and assessed the effects of exchanging from an ARB to aliskiren on home blood pressure in hypertensive patients with diabetic nephropathy on chronic hemodialysis. The patients who were persistently hypertensive despite antihypertensive therapy, including ARB, were considered as candidates for the exchange from the ARB to aliskiren. Patients' age and durations of diabetes and hemodialysis were averaged as 62 ± 9 years old, 15 ± 8 and 7 ± 3 years, respectively. Aliskiren decreased morning systolic blood pressure (149 ± 14 to 144 ± 13 mm Hg, n = 30, P < .01) and plasma renin activity (3.5 ± 1.1 to 1.2 ± 0.6 ng/mL/h, P < .01) without changes in serum potassium. Aliskiren also reduced interdialytic weight gain (2.7 ± 0.6 to 2.5 ± 0.5 kg/interval, P < .05) and attenuated the magnitude of intradialytic declines in systolic (-20 ± 11 to -17 ± 10 mm Hg, P < .05) and diastolic blood pressure (-9 ± 6 to -5 ± 5 mm Hg, P < .01). The exchange from an ARB to aliskiren is safe and useful to control home blood pressure in hypertensive hemodialysis patients with diabetic nephropathy. Aliskiren reduced both intradialytic blood pressure drops and interdialytic weight gain in patients with DN.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Blood Pressure; Circadian Rhythm; Diabetic Nephropathies; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Renal Dialysis; Renin; Retrospective Studies; Weight Gain

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Fumarates; Heart Failure; Humans; Renin; Stroke Volume; Ventricular Dysfunction, Left

Aliskiren, a direct renin inhibitor (DRI), has therapeutic effects in patients with hypertension and associated complications, but its potential mechanism in diabetic nephropathy is lacking. The effects of aliskiren in Streptozotocin (STZ)-induced renal complication in diabetic rats were investigated. Aliskiren treatment for eight weeks at the dose of 10 mg/kg/day, via osmotic mini-pump, induced improvement in blood glucose levels, systolic blood pressure (BP) and serum creatinine. Improvement of insulin resistance by aliskiren was confirmed by increased glucose translocation in liver and muscle and hence insulin levels. The treated group also showed improvement in glomerulosclerosis and tubulointerstitial injury. Aliskiren treatment also improved albumin levels in plasma, suppressed profibrotic and proinflammatory cytokine synthesis viz TNF-α and TGF-β and angiogenesis by a decrease in VEGF. In addition, the level of total proteins and GFR via cystatin c and beta-2microglobulin along with adiponectin and erythropoietin were also improved. These results suggest that the beneficial organ protective effect of aliskiren is mediated by improvement in insulin resistance as well as a direct anti-fibrotic effect in the target organ in STZ-induced diabetic rats with a slight effect on blood pressure. Aliskiren may be a useful therapeutic agent in the treatment of type 2 diabetes and diabetic nephropathy.

Topics: Amides; Animals; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Nephropathies; DNA Fragmentation; Extracellular Matrix; Fumarates; Glomerular Filtration Rate; Glucose Transporter Type 2; Glucose Transporter Type 4; Hemodynamics; Humans; Inflammation; Insulin; Insulin Resistance; Liver; Mice; Muscles; Rats; Rats, Wistar; ROC Curve

Aldosterone is increased in diabetes and contributes to the development of diabetic nephropathy. The authors hypothesized that reduction in aldosterone production in diabetes by amlodipine or aliskiren improves diabetic kidney disease by attenuating renal oxidative stress and fibrosis. Normoglycemic and streptozotocin-induced diabetic Sprague-Dawley rats were given vehicle, amlodipine, or aliskiren alone and combined for 6 weeks. At the end of study, we evaluated blood pressure (BP), 24-hour urinary sodium (UNaV) and aldosterone excretion rates, renal interstitial fluid (RIF) levels of nitric oxide (NO), cyclic guanosine 3',5'-monophosphate (cGMP), and 8-isoprostane, and renal morphology. BP was not significantly different between any of experimental groups. UNaV increased in diabetic animals and was not affected by different treatments. Urinary aldosterone excretion increased in diabetic rats receiving vehicle and decreased with amlodipine and aliskiren alone or combined. RIF NO and cGMP levels were reduced in vehicle-treated diabetic rats and increased with amlodipine or aliskiren given alone and combined. RIF 8-isoprostane levels and renal immunostaining for periodic acid-Schiff and fibronectin were increased in vehicle-treated diabetic rats and decreased with aliskiren alone or combined with amlodipine. The authors conclude that inhibition of aldosterone by amlodipine or aliskiren ameliorates diabetes induced renal injury via improvement of NO-cGMP pathway and reduction in oxidative stress and fibrosis, independent of BP changes.

Topics: Aldosterone; Amides; Amlodipine; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Cyclic GMP; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dinoprost; Down-Regulation; Fibronectins; Fibrosis; Fumarates; Immunohistochemistry; Kidney; Male; Natriuresis; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Time Factors

Diabetic nephropathy is one of the major causes of chronic kidney disease (CKD), consequently progression to end stage renal disease. The previous studies demonstrated that the inhibition on renin-angiotensin-aldosterone system (RAAS) such as by angiotensin converting enzyme inhibitor (ACEI) and angiotensin type I receptor blocker (ARB) reduced proteinuria and slow progression of CKD. Direct renin inhibitor (DRI) theoretical complete block RAAS by reducing plama renin activity angiotensin I and angiotensin II. The present study aimed to determine the efficacy of aliskiren (DRI) monotherapy on blood pressure control and proteinuria reduction.. Diabetic mellitus patients with estimated glomerular filtration rate (eGFR) > or = 30 ml/min who had proteinuria > 300 mg/day were enrolled to receive aliskiren 150 mg/day for 2 weeks then 300 mg/day until 24 weeks.. The SBP were significantly decreased form 137.8 to 123.7 (p = 0.01) at 2 weeks, 137.8 to 126.26 (p = 0.04) at 4 weeks and 137.8 to 121 mmHg (p = 0.002) at 24 weeks after treatment, respectively. Similar to SBP, the DBP was significantly decreased from 84.08 to 73.66 (p = 0.04) at 4 weeks and 84.08 to 75.85 mmHg (p = 0.002) at the end of study. Reduction of UPCR showed significantly reduced for 32.65% (p = 0.007) and 45% (p = 0.004) from baseline at 2 weeks and 24 weeks after DRI treatment respectively. Serum creatinine, eGFR and serum potassium were no significant changed from the baseline. There were no harmful adverse reaction in patients who receiving aliskirin.. Aliskiren monotherapy showed significantly reduced proteinuria, good blood pressure control without harmful side effect in overt diabetic nephropathy patients.

Topics: Aged; Amides; Antihypertensive Agents; Diabetic Nephropathies; Female; Fumarates; Humans; Male; Middle Aged; Prospective Studies; Proteinuria; Renin

Diabetic nephropathy (DN) is a leading disease that requires renal replacement therapy. The progression of renal dysfunction in DN is faster than the other renal diseases. While antihypertensive therapy reduces albuminuria, a good indicator for the progression, hypertension in DN is treatment resistant. Among patients with DN who took angiotensin receptor blockers (ARBs), 27 patients who exhibited poor control of albuminuria were enrolled into the study. Angiotensin receptor blocker was exchanged to aliskiren (150-300 mg/d) and clinical parameters were followed for 6 months. Exchange to aliskiren decreased albuminuria (1.57 ± 0.68 to 0.89 ± 0.45 g/gCr, P < .01) without changes in estimated glomerular filtration rate and office blood pressure (BP). Body weight and hemoglobin A1c were not altered. Aliskiren also reduced plasma renin activity (2.0 ± 0.9 to 1.2 ± 0.6 ng/mL/h, P < .01). While evening BP was unchanged, morning systolic BP (139 ± 8 to 132 ± 7 mm Hg, P < .01) and diastolic BP (81 ± 7 to 76 ± 6 mm Hg, P < .05) were decreased significantly after 6 months. Our results indicated that aliskiren decreased BP, especially morning BP in hypertensive patients with DN. The present data suggest that aliskiren exerts renoprotective actions including reduction in albumin excretion for patients with DN.

Topics: Aged; Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Circadian Rhythm; Diabetic Nephropathies; Disease Progression; Female; Fumarates; Glomerular Filtration Rate; Humans; Male; Middle Aged; Prospective Studies; Renin

Aliskiren is the first in a new class of orally active direct renin inhibitors, approved for the treatment of hypertension. However, the efficacy of aliskiren in diabetic cardiovascular complications remains to be defined. This study aimed to test the hypothesis that aliskiren may enhance the beneficial effects of pioglitazone against cardiovascular injury associated with diabetic nephropathy.. Diabetic nephropathy was induced in rats by unilateral nephrectomy followed by streptozotocin injection. Diabetic nephropathic rats were orally given vehicle, pioglitazone, aliskiren, or combined pioglitazone and aliskiren for four weeks to compare their effects on cardiovascular injury, particularly myocardial fibrosis.. Pioglitazone treatment significantly attenuated cardiac lipid peroxidation, oxidative injury and myocardial fibrosis in diabetic nephropathic rats. This was associated with up-regulation of transforming growth factor-β1 and matrix metalloproteinase-2 genes, along with down-regulation of tissue inhibitor of metalloproteinase-2 gene in cardiac tissue. The combination of aliskiren with pioglitazone exerted greater beneficial effect than monotherapy with either drug, on all the aforementioned parameters.. Our findings suggested that aliskiren enhanced the protective effects of pioglitazone against myocardial fibrosis, in experimental diabetic nephropathy. Thus, the combination of aliskiren and pioglitazone may be a potential therapeutic strategy for cardiovascular injury associated with diabetic nephropathy.

Topics: Amides; Animals; Antihypertensive Agents; Cardiomyopathies; Diabetic Nephropathies; Disease Models, Animal; Drug Therapy, Combination; Fibrosis; Fumarates; Gene Expression Regulation; Hypoglycemic Agents; Lipid Peroxidation; Male; Matrix Metalloproteinase 2; Myocardium; Nephrectomy; Oxidative Stress; Pioglitazone; Rats; Rats, Wistar; Streptozocin; Thiazolidinediones; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta1

Aliskiren is a direct renin inhibitor (DRI) and provides an organ-protective effect in human and animal experiments. However, there is no current evidence of the effect of DRI on insulin resistance and metabolic abnormalities in type 2 diabetic animals. Methods. We investigated the effects and molecular mechanism of aliskiren in db/db mice and cultured mesangial cells (MCs).. Aliskiren treatment for 3 months at a dose of 25 mg/kg/day via an osmotic mini-pump did not induce significant changes in blood glucose levels, systolic blood pressure, serum creatinine and electrolyte levels. However, aliskiren treatment improved insulin resistance confirmed by insulin tolerance test and various biomarkers including homeostasis model assessment index levels and lipid abnormalities. The treated group also exhibited significant improvement in cardiac functional and morphological abnormalities including left ventricular hypertrophy, and induced phenotypic changes in adipose tissue. Aliskiren treatment also markedly decreased urinary albumin excretion, glomerulosclerosis and suppressed profibrotic and proinflammatory cytokine synthesis and improved renal lipid metabolism. In cultured MCs, high glucose stimulation increased MC renin concentration. Furthermore, renin treatment directly up-regulates synthesis of proinflammatory and profibrotic cytokines, which were abolished by prior treatment with aliskiren and angiotensin receptor (AT1) antagonist. These results suggest that the beneficial effect of aliskiren is mediated by an angiotensin-dependent mechanism.. Together, these results imply that aliskiren provides an organ-protective effect through improvement in insulin resistance and lipid abnormality, as well as direct anti-fibrotic effect in target organ in db/db mice. Aliskiren may be a useful new therapeutic agent in the treatment of type 2 diabetes mellitus and diabetic nephropathy.

Topics: Amides; Animals; Biomarkers, Tumor; Blood Glucose; Blood Pressure; Blotting, Western; Body Weight; Cells, Cultured; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Fumarates; Gene Expression Profiling; Humans; Immunoenzyme Techniques; Insulin; Insulin Resistance; Male; Mesangial Cells; Mice; Mice, Mutant Strains; Oligonucleotide Array Sequence Analysis; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Amides; Antihypertensive Agents; Asian People; Blood Pressure; Chemokine CCL2; Creatinine; Deoxyguanosine; Diabetic Nephropathies; Female; Fumarates; Glomerular Filtration Rate; Humans; Interleukin-6; Male; Middle Aged; Oxidative Stress; Treatment Outcome

Altered extracellular matrix (ECM) remodeling and podocyte apoptosis are characteristic features of diabetic nephropathy (DN). Aliskiren (ALI) inhibits the renin-catalyzed conversion of angiotensinogen to angiotensin I. This study tested ALI's effect on podocyte ECM accretion and survival in a high-glucose environment in vitro.. Conditionally immortalized mouse podocytes were incubated in normal glucose (NG; 5.5 mM) or high glucose (HG; 40 mM) for 24-48 h with and without ALI (20 nM). Real-time RT-PCR was performed for fibronectin (FN), collagen α5(type IV) (Cola5IV), matrix metalloproteinases 2 and 9 (MMP2 and MMP9), and tissue inhibitor of metalloproteinases 1 and 2 (TIMP1 and TIMP2). Western blots were performed for FN, Cola5IV, MMP2, MMP9, TIMP1 and cleaved (activated) caspase-3.. ALI significantly reduced the mRNA and protein levels of FN, Cola5IV and TIMP1, and the mRNA of TIMP2 and cleaved caspase-3. ALI had no effect on MMP2 mRNA or protein or MMP9 mRNA tested under HG conditions. Under NG conditions, ALI had no effect on FN, Cola5IV, MMP2, MMP9 and activated caspase-3 proteins. ALI decreased the activated caspase-3 protein and evidence of apoptosis by TUNEL staining observed in podocytes cultured under HG conditions.. These results show for the first time that renin inhibition with ALI mitigates the profibrotic and apoptotic effects of HG in cultured podocytes. These data strengthen the therapeutic rationale for renin inhibition with ALI beyond its hemodynamic effects.

Topics: Amides; Animals; Apoptosis; Cells, Cultured; Collagen Type IV; Diabetic Nephropathies; Extracellular Matrix; Fibronectins; Fumarates; Glucose; Matrix Metalloproteinases; Podocytes; Renin; RNA, Messenger

Addition of aliskiren, a direct renin inhibitor, to losartan provides additive reduction of urinary albumin excretion in type 2 diabetic patients. However, the detailed effect of aliskiren on type 2 diabetic nephropathy is still unknown. This study was undertaken to examine the efficacy of aliskiren and the combination of aliskiren with valsartan on type 2 diabetic nephropathy.. db/db mice were treated with aliskiren (3 mg/kg per day), valsartan (5 or 10 mg/kg per day), combined aliskiren (3 mg/kg per day) and valsartan (5 mg/kg per day), and hydralazine (80 mg/kg per day), for 6 weeks, and the protective effects against diabetic nephropathy were compared among each group.. Aliskiren significantly attenuated albuminuria and glomerular mesangial matrix expansion in db/db mice, which was associated with the improvement of the increased glomerular transforming growth factor-beta and type IV collagen expressions, the increased macrophage infiltration, and the decreased glomerular nephrin expression of db/db mice. These protective effects of aliskiren in db/db mice were attributed to the attenuation of p22(phox)-related nicotinamide adenine dinucleotide phosphate oxidase-induced superoxide. Addition of aliskiren to valsartan treatment provided more beneficial effects on all the above-mentioned parameters than valsartan monotherapy.. Aliskiren protected against type 2 diabetic nephropathy, through pleiotropic effects, and significantly enhanced the protective effects of valsartan against diabetic nephropathy in db/db mice.

Topics: Albuminuria; Amides; Animals; Collagen Type IV; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Synergism; Fumarates; Kidney Glomerulus; Losartan; Male; Mice; Mice, Inbred C57BL; Tetrazoles; Transforming Growth Factor beta; Valine; Valsartan

The Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial demonstrated that adding aliskiren, an oral direct renin inhibitor, at a dosage of 300 mg/d to the highest approved dosage of losartan and optimal antihypertensive therapy reduces albuminuria over 6 mo among patients with type 2 diabetes, hypertension, and albuminuria. The cost-effectiveness of this therapy, however, is unknown. Here, we used a Markov model to project progression to ESRD, life years, quality-adjusted life years, and lifetime costs for aliskiren plus losartan versus losartan. We used data from the AVOID study and the Irbesartan in Diabetic Nephropathy Trial (IDNT) to estimate probabilities of progression of renal disease. We estimated probabilities of mortality for ESRD and other comorbidities using data from the US Renal Data System, US Vital Statistics, and published studies. We based pharmacy costs on wholesale acquisition costs and based costs of ESRD and transplantation on data from the US Renal Data System. We found that adding aliskiren to losartan increased time free of ESRD, life expectancy, and quality-adjusted life expectancy by 0.1772, 0.1021, and 0.0967 yr, respectively. Total expected lifetime health care costs increased by $2952, reflecting the higher pharmacy costs of aliskiren and losartan ($7769), which were partially offset by savings in costs of ESRD ($4860). We estimated the cost-effectiveness of aliskiren to be $30,500 per quality-adjusted life year gained. In conclusion, adding aliskiren to losartan and optimal therapy in patients with type 2 diabetes, hypertension, and albuminuria may be cost-effective from a US health care system perspective.

Topics: Albuminuria; Amides; Biphenyl Compounds; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Fumarates; Health Care Costs; Humans; Hypertension; Irbesartan; Losartan; Quality-Adjusted Life Years; Tetrazoles

Renin-angiotensin aldosterone system has a detrimental effect on the progression of renal failure in patients with chronic kidney disease. Drugs inhibiting the renin-angiotensin aldosterone system, such as angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers have been shown to slow the progression of kidney disease in patients with diabetic and nondiabetic renal diseases. Aliskiren is a direct renin inhibitor that blocks the renin-angiotensin system at its initial step. Several experimental studies have demonstrated the renoprotective effects of aliskiren. Aliskiren, added to standard therapy, shows additional and significant antiproteinuric effects in patients with diabetic nephropathy. The optimal therapeutic approach to patients with target organ damage will be better understood as the ongoing large clinical studies with direct renin inhibitors conclude.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetic Nephropathies; Fumarates; Humans; Kidney Diseases; Proteinuria; Renin; Renin-Angiotensin System

Aliskiren (Rasilez), a direct renin inhibitor, is currently indicated for the treatment of essential hypertension, as monotherapy or in combination, especially with hydrochlorothiazide (Rasilez HCT). It may also be use to obtain a more complete blockade of the renin-angiotensin-aldosterone system (RAAS) when it is associated with an angiotensin converting enzyme inhibitor (ACEI) (or an AT1 angiotensin receptor antagonist) (ARA). There is some room for agents that may be more efficacious in reducing the progression of diabetic nephropathy than ACEI or ARA. In this context, the dual blockade of RAAS most probably offers a better efficacy than the simple blockade, but also exposes to a higher risk. Should ongoing trials confirm the preliminary favourable results, aliskiren might reach a forefront position among the armamentarium now available to optimize the RAAS blockade. The present article will summarize advances concerning the biochemical effects of the specific mode of action of aliskiren, especially the potential interferences related to increased renin/pro-renin levels, as well as results of recent clinical trials, not only in hypertension, but also in the fields of diabetes, renal insufficiency and cardiology. The objectives and design of the landmark study ALTITUDE will also be briefly presented.

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetic Nephropathies; Fumarates; Humans; Renin

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Fumarates; Humans; Losartan; Proteinuria; Renin; Renin-Angiotensin System

Topics: Amides; Antidepressive Agents; Antihypertensive Agents; Contraindications; Diabetic Nephropathies; Female; Fumarates; Health Promotion; Heart Diseases; Humans; Natriuretic Peptide, Brain; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Renin; Smoking; Smoking Prevention

The aim of this study was to explore the effects of the renin inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between renin and the (pro)renin receptor and between aliskiren and prorenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor-beta and collagen I expression versus vehicle. Aliskiren reduced (pro)renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 micromol/L to 10 micromol/L) did not inhibit binding of (125)I-renin to the (pro)renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)renin receptor. Evidence was obtained that aliskiren binds to the active site of prorenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)renin receptor and that it may block prorenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this renin inhibitor.

Topics: Albuminuria; Amides; Animals; Antihypertensive Agents; Blood Pressure; Collagen Type I; Collagen Type III; Collagen Type IV; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fumarates; Gene Expression; Humans; Male; Prorenin Receptor; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Renin; Transforming Growth Factor beta

Topics: Amides; Animals; Antihypertensive Agents; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fumarates; Hypertension; Rats; Renin

Blockade of the renin-angiotensin system (RAS) with either ACE inhibitors or angiotensin receptor blocker is a key therapeutic strategy in slowing progression of diabetic nephropathy. Interruption of the RAS may also be achieved by blocking the activity of renin, the rate-limiting step in angiotensin II biosynthesis. However, it is not known whether drugs in this class also reduce the structural and functional manifestations of diabetic nephropathy.. Using diabetic transgenic (mRen-2)27 rats, a rodent model of advanced diabetic nephropathy, we compared the efficacy of the renin inhibitor, aliskiren (10 mg kg(-1) day(-1) by osmotic mini-pump), with the ACE inhibitor, perindopril (0.2 mg kg(-1) day(-1) in drinking water), over a 16 week period.. Both perindopril and aliskiren reduced blood pressure, albuminuria and structural injury in experimental diabetic nephropathy, although not to the same extent. Aliskiren, at the dose used, did not reduce systemic blood pressure as much as perindopril, but both compounds were equally effective in reducing albuminuria and glomerulosclerosis in diabetic animals. The magnitude of interstitial fibrosis was attenuated to a greater degree by aliskiren than by perindopril.. These findings suggest that therapies aimed at different targets within the RAS may not have identical effects in attenuating structural injury in experimental diabetic nephropathy.

Topics: Aldosterone; Amides; Animals; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Female; Fumarates; Kidney; Organ Size; Rats; Rats, Inbred Strains; Renin