UMLS:C0033687 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
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The renin-angiotensin-aldosterone system (RAAS) plays an important part in the pathogenesis of arterial hypertension and the complications it causes in organs (the heart, the circulatory system, the brain, the kidneys), heart failure and kidney diseases. Materials that block the most upstream point of the RAAS cascade (ACE inhibitors - ACEI, AT1,-receptor (AT1R) blockers, aldosterone receptor blockers) have greatly expanded our options in the treatment and primary and secondary prevention of cardiovascular and renal diseases. ACEI and AT1R blockers interrupt the normal feedback provided by the release of renin into the circulatory system from the kidneys. After they are applied the reactive increase in active circulating renin leads to increased creation of angiotensin I and angiotensin II and the subsequent return of aldosterone secretions to pre-treatment values ("escape" phenomenon). The possible negative effect of these intermediary products of an incomplete blockade of RAAS on organ complications lead to an effort to develop a material that could block the renin-angiotensin cascade at its first stage--i.e. a renin blocker. The first efforts with renin antibodies or peptide analogues of renin prosegments failed to satisify the basic requirements for long-term medication--effectiveness when used orally. In recent years the first non-peptidic, oral renin ihibitor providing sustained effects has been developed, aliskiren fumarate. Aliskiren reduces BP depending on the dose (50-300 mg/day) in monotherapy or in combination with hydrochlorothiazide. Aliskiren lowers plasma renin activity (PRA) and neutralises the activation of the RAAS triggered by hydrochlorothiazide. Ambulatory BP monitoring has shown that taking the medicine once a day has a 24-hour effect and its continued residence in the kidneys suggests renoprotective effects. The compound is in the third stage of clinical tests as a monotherapy or in combination for the treatment of hypertension. It has also been shown to have an influence on the regression of cardiac hypertrophy (Aliskiren in Left-Ventricular Hypertrophy trial - ALLAY), the treatment of heart failure (Aliskiren Observation of Heart Failure Treatment trial - ALOFT) and diabetic (Aliskiren in the Evaluation of Proteinuria in Diabetes trial - AVOID). In April 206, the FDA permitted the use of aliskiren in the USA for the treatment of high BP and it is currently undergoing testing in Europe. The renin inhibitor has minimal undesirable side effects, like AT1-receptor blockers. The slightly lower effectiveness ofaliskiren than AT1-receptor blockers in reducing BP is caused by the fact that it does not block bradykinins. It is recommended as a monotherapy for clinical use or in combination with other antihypertensive medicines for conditions with high levels of PRA including its rise after diuretics, ACEI and AT1-receptor blockers. Aliskiren could therefore be used primarily with young patients, Caucasians, persons with ACEI intolerance, and also in diseases where angiotensin II is involved in the pathogenesis and the secondary prevention of cardiovascular disease. It is also safe for persons with concurrent renal problems, because it is mainly removed by the liver without great interference with other materials. Like ACEI, the renin inhibitor has a vasodilatory effect which could potentially improve the elasticity of arteries. The medicine has the same limitations and contraindications as ACEI and AT1R blockers, such as pregnancy and bilateral renal artery stenosis. A definitive assessment of the benefit of this new class of medicines and its broad application in the treatment of cardiovascular and other diseases will require demonstration of its long-term effect on morbidity and mortality, as well as comparison with other RAAS blockers in long clinical studies, which represent research programmes lasting another 7 to 8 years.
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PMID:[Does the rennin inhibitor aliskiren offer promising novel opportunities in the treatment of cardiovascular diseases?]. 1757 67

The development of aliskiren, the first orally effective renin inhibitor, utilized molecular modeling based upon X-ray crystallographic analysis of renin's active site to design a potent, low molecular weight renin inhibitor with improved bioavailability (approximately 2.6%). In patients with hypertension, dose-dependent BP reduction occurs with aliskiren 75-300 mg once daily; at these doses, the safety and tolerability profile is comparable to placebo. In direct comparison studies, BP reduction with aliskiren is equivalent to commonly used antihypertensive agents including diuretics, ACE inhibitors, and ARBs. Persistent BP reduction and prolonged suppression of plasma renin activity (PRA) is observed after aliskiren withdrawal. Aliskiren suppresses PRA when given either as monotherapy or in combination with other agents. When added to an ARB, aliskiren blocks compensatory RAS activation and produces significant additional BP reduction. In patients with diabetic nephropathy, addition of aliskiren to losartan, 100 mg resulted in a 20% greater reduction in proteinuria. Ongoing studies evaluating the long-term renal protective effects of aliskiren and its effects on ventricular remodeling are currently planned or underway.
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PMID:Current concepts: renin inhibition in the treatment of hypertension. 1830 34

Hypertension is one of the major health care problems worldwide since it markedly increases the risk for development of heart disease, stroke, generalized vascular disease, and renal failure. The renin-angiotensin system (RAS) with its major end-product angiotensin II (Ang II) plays a fundamental role in blood pressure regulation through direct and indirect mechanisms. Pharmacologically, we can inhibit the RAS using angiotensin-converting enzyme inhibitors and AT1 receptor blocker. Inhibiting renin directly with a clinically useful drug eluded pharmacologists until recently. However, the once-daily, orally effective, small-molecule, direct renin inhibitor aliskiren has recently changed this state of affairs. Aliskiren, with its 40-h half-life and ideal pharmacokinetics, can now address angiotensin production directly at its rate-limiting step. A novel transgenic rat model outfitted with the human renin and angiotensinogen genes allowed the testing of aliskiren in an animal model. Preclinical data demonstrated that aliskiren prolonged survival, decreased cardiac hypertrophy and the inducibility of arrhythmias, proteinuria, and attenuated inflammation. All these features might result in improved target-organ damage. Studies in humans attest to an effective blood pressure-lowering action, a largely side effect-free profile, and the option of several combination therapies. Aliskiren is the first of a novel antihypertensive drug class. The preclinical data is very promising. Nevertheless, for the evaluation of its potency in humans, we have to wait for more clinical data.
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PMID:Aliskiren--mode of action and preclinical data. 1844 51

Chronic kidney disease (CKD), a major worldwide public-health problem which affects about 10% of the population, has an increased annual incidence rate of about 5-8%. This increased incidence is mainly due to type 2 diabetes and hypertension and the increasing incidence of elderly patients with CKD. Although the progression to end-stage renal failure (ESRF) is mainly based upon the underlying disease, comorbid conditions such as an initial low renal function, severe proteinuria, and high levels of blood pressure also play important roles in the development of ESRF. Since experimental and clinical evidence suggest that angiotensin II plays a central role in the progression of CKD, pharmacological inhibition of the renin-angiotensin-aldosteron system (RAAS) with angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists has been suggested as first-line treatment for hypertension and prevention of ESRF in these patients. Aliskiren, a novel renin inhibitor is also a promising medical intervention. However, independently of the category of the drugs used, low target blood pressure levels seem to be equally or more important for the delay or prevention of CKD. In this review the results of studies with pharmacological inhibition of the RAAS in patients with diabetic and nondiabetic nephropathy is discussed.
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PMID:Inhibition of the renin-angiotensin system and chronic kidney disease. 1880 6

The renin-angiotensin-aldosterone system (RAAS) is an important mediator of blood pressure (BP) and volume regulation in both normotensive and hypertensive persons and is a major contributor to hypertension-related target organ damage. The concept of renin inhibition for managing hypertension by blocking the RAAS pathway at its point of activation is very attractive since the renin-angiotensinogen reaction is the first and rate-limiting step in the generation of angiotensin II (Ang II). Aliskiren, the first in a new class of orally effective direct renin inhibitors (DRIs), is approved for the treatment of hypertension. It is effective in reducing BP in the general population of hypertensive patients and in special patient groups such as obese persons, and has a tolerability and safety profile similar to placebo. Aliskiren has renoprotective, cardioprotective and anti-atherosclerotic effects in animal models that appear to be independent of BP lowering. It reduces proteinuria in diabetic patients and has favorable neurohumoral effects in patients with symptomatic heart failure. Additional outcome trials are needed to establish the role of this novel class of antihypertensive medication in the therapeutic armamentarium.
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PMID:Role of aliskiren in cardio-renal protection and use in hypertensives with multiple risk factors. 1947 81

Combining an angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) lowers blood pressure (BP) by 4/3 mmHg compared to either agent alone, although this additive effect may be abolished with maximal monotherapy dosing. The recent ONTARGET study showed no reduction in primary outcomes when an ACE-I-ARB combination was compared to an ACE-I alone, despite 2.4/1.4 mmHg lower BP in the former group. In proteinuric chronic kidney disease, an ACE-I-ARB combination reduces proteinuria and disease progression more than monotherapy, but the ONTARGET study showed an increase in renal endpoints in the combined group. Aliskiren offers a novel approach to renin-angiotensin system (RAS) inhibition. As monotherapy in hypertension, aliskiren is of similar efficacy to thiazides, calcium channel blockers and ARBs. In combination with other RAS inhibitors at maximal dosage aliskiren has a small synergistic effect on BP (additional 4/2 mmHg reduction). Early data suggest a role for aliskiren in preventing end-organ damage but, considering the ONTARGET results with an ACE-I-ARB combination, outcome studies are needed before the use of aliskiren can be recommended in combination with other RAS inhibitors. As monotherapy, aliskiren should probably be reserved for use as an alternative to ACE-Is or ARBs, where these are ineffective or poorly tolerated.
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PMID:Combination renin-angiotensin system blockade with the renin inhibitor aliskiren in hypertension. 1961 73

The renin-angiotensin-aldosterone system (RAAS) is a key mediator of blood pressure (BP) and volume regulation in both normotensive and hypertensive persons. Stimulation of RAAS also contributes to hypertension-related target organ damage. The renin-angiotensinogen reaction is the first and rate-limiting step in the generation of angiotensin II (Ang II) and has been a target of antihypertensive drug development for decades. Aliskiren is the first in a new class of orally effective direct renin inhibitors (DRIs) and is approved for the treatment of hypertension in humans. It effectively reduces BP in the general population of hypertensive patients and has a tolerability and safety profile similar to placebo. Aliskiren has favorable effects on vascular inflammation and remodeling, on neurohumoral mediators of various forms of cardiovascular disease, including heart failure, and on proteinuria in diabetic patients. Additional outcome trials are needed to establish the role of this novel class of antihypertensive medication in preventing cardiovascular disease morbidity and mortality.
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PMID:Role of aliskiren in cardio-renal protection and use in hypertensives with multiple risk factors. 1970 55

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.
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PMID:Cost-effectiveness of aliskiren in type 2 diabetes, hypertension, and albuminuria. 1976 96

The three main causes of Chronic Kidney Diseases [CKD] are diabetes mellitus, chronic glomerulonephritis and hypertension. CKD is an increasing burden in the community as more patients fall prey to kidney failure. Both dialysis and renal transplantation are expensive modalities of treatment for end stage renal failure [ESRF]. Through the years many clinical trials have been performed to retard the progression of CKD to ESRF. Most of the trials focus on three main strategies which aim at renal retardation, namely, control of hypertension, treatment of proteinuria and control of hypercholesterolaemia. More recently, investigators have been exploring the role of high dose ARBs as well as the use of Aliskiren, a renin inhibitor. Early therapeutic intervention is necessary as it will contribute to better chances of minimising glomerular damage and in the case of some, even lead to the improvement of renal function with regression of glomerulosclerosis.
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PMID:Clinical trials of the past decade in the management of chronic kidney disease. 2002 26

The role of renin-angiotensin-aldosterone system (RAAS) in regulating the volume and composition of extracellular fluid, blood pressure (BP) as well as onset and progression of cardiovascular and renal diseases has been studied for more than 150 years. The compounds that block the vital stages of the RAAS cascade, such as ACE-inhibitors (ACEI), AT1-receptor blockers (ARB) and aldosterone receptor antagonists, importantly extended our treatment options. However, the positive therapeutic effects of these compounds also have certain negative consequences. Administration of ACEIs and ARBs interrupts physiological feedback for renal renin release and leads to reactive elevation of circulating active renin and greater production of angiotensin I and angiotensin II with subsequent return of aldosterone secretion to the pre-treatment levels ('escape' phenomenon). These possible adverse effects of the intermediary products of incomplete RAAS blockade leading to organ complications have facilitated the efforts to develop compounds blocking the initial stages of renin-angiotensin cascade--i.e. direct renin blockers. After several years of unsuccessful attempts, the recent years have seen development of the first non-peptide, orally long-term effective renin inhibitor, aliskiren fumarate. In monotherapy or in combination with other antihypertensives (hydrochlorothiazide, ARB, ACEI), aliskiren reduces BP in a dose-dependent manner (75-600 mg/den). Aliskiren reduces plasma renin activity (PRA) and neutralises hydrochlorothiazide-induced RAAS activation. Once daily administration of the drug leads to longer than 24-hour activity and its prolonged blocking effects on the kidneys are the basis for its renoprotectivity. In addition to the significant antihypertensive effect, clinical studies also showed a range of organoprotective properties in patients with left ventricle hypertrophy (ALLAY study), heart failure (ALOFT study) and diabetic nephropathy (AVOID study). Similar to other AT1-blockers, aliskiren has a minimum of adverse side effects. Aliskiren for hypertension therapy was launched in clinical practice in USA in 2007 (Tekturna and combination formulation TekturnaHCl, respectively) and shortly after that in European Union as Rasilez. In the Czech Republic, aliskiren (Rasilez) was released for clinical use by diabetologists and nephrologists in patients with hypertension and concomitant diabetes, nephropathy and proteinuria in doses of 150-300 mg per day on 1. 8. 2009. It is recommended as monotherapy or in combination with other antihypertensives to treat conditions with elevated PRA, including PRA elevation following diuretic, ACEI or ARB administration. Aliskiren might be used in patients who do not tolerate ACEIs as well as in patients in whom angiotensin II participates in the pathogenesis of their diseases. Reno-protective properties leading to a reduction in proteinuria and delaying renal failure progression were observed in patients with diabetic as well as non-diabetic nephropathy. The drug is the subject to similar precautions and contraindications as ACEIs and ARBs, i.e. pregnancy and bilateral renal artery stenosis. To make meaningful conclusions about the so far positive contribution of this new treatment class and its broad applicability for the therapy of hypertension and other cardiovascular diseases, it will be imperative to assess its long-term effects on morbidity and mortality as well as to compare these agents with other RAAS blockers in long-term clinical studies; this represents a research effort for another 7-8 years.
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PMID:[Direct renin inhibitor aliskiren in the treatment of cardiovascular and renal diseases]. 2032 82

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