Triple Pharmacological Blockade of the Renin-Angiotensin-Aldosterone System in Nondiabetic CKD: An Open-Label Crossover Randomized Controlled Trial

Tylicki, Leszek; Rutkowski, Przemysław; Renke, Marcin; Larczyński, Wojciech; Aleksandrowicz, Ewa; Łysiak−Szydłowska, Wiesława; Rutkowski, Bolesław

doi:10.1053/j.ajkd.2008.02.297

Cited by 92 publications

(71 citation statements)

References 28 publications

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“…104 Of interest, the antiproteinuric effect was not confined to participants with aldosterone breakthrough. 105 However, these encouraging findings are tempered by the excess risk of hyperkalemia particularly in patients with decreased GFR. Thus, long-term efficacy and safety data are needed before aldosterone antagonism therapy can be recommended in the wider nephrology context.…”

Section: What Is New In the Pipeline?mentioning

confidence: 99%

Mechanisms and Treatment of CKD

Ruggenenti

Cravedi

Remuzzi

2012

Journal of the American Society of Nephrology

233

182

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As CKD continues to increase worldwide, along with the demand for related lifesaving therapies, the financial burden of CKD will place an increasing drain on health care systems. Experimental studies showed that glomerular capillary hypertension and impaired sieving function with consequent protein overload play a pathogenic role in the progression of CKD. Consistently, human studies show that proteinuria is an independent predictor of progression and that its reduction is renoprotective. At comparable BP control, inhibitors of the renin-angiotensin system (RAS), including angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), more effectively than non-RAS inhibitor therapy reduce proteinuria, slow progression to ESRD, and even improve the kidney function achieving disease regression in some cases. In participants with diabetes, RAS inhibitors delay the onset of microalbuminuria and its progression to macroalbuminuria, and ACE inhibitors may reduce the excess cardiovascular mortality associated with diabetic renal disease. In addition to RAS inhibitors, however, multimodal approaches including lifestyle modifications and multidrug therapy will be required in most cases to optimize control of the several risk factors for CKD and related cardiovascular morbidity. Whether novel medications may help further improve the cost-effectiveness of renoprotective interventions is a matter of investigation.

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Section: What Is New In the Pipeline?mentioning

confidence: 99%

Mechanisms and Treatment of CKD

Ruggenenti

Cravedi

Remuzzi

2012

Journal of the American Society of Nephrology

233

182

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“…Eight studies included diabetic patients; the large study of Bianchi et al included patients with various forms of glomerulonephritis (23); the remaining two studies included patients with nondiabetic renal disease encompassing IgA nephropathy, benign nephrosclerosis, and membranous nephropathy (35,36). All studies excluded patients with GFR Ͻ30 ml/mim/1.73m 2 .…”

Section: Trial Characteristicsmentioning

confidence: 99%

“…The majority of the included studies enrolled few patients and were powered to observe differences in surrogate end-points rather than patient-focused outcomes. Five studies had a cross-over design (26,27,33,34,36) and most did not adequately report study methods to assess methods and trial quality.…”

Section: Strengths and Limitationsmentioning

confidence: 99%

Aldosterone Antagonists for Preventing the Progression of Chronic Kidney Disease

Navaneethan

Nigwekar

Sehgal³

et al. 2009

Clinical Journal of the American Society of Nephrology

227

132

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Background and objectives: Addition of aldosterone antagonists (AA) might provide renal benefits to proteinuric chronic kidney disease (CKD) patients over and above the inhibition of renin-angiotensin system blockers (RAS). We evaluated the benefits and harms of adding selective and nonselective AA in CKD patients already on RAS.Design, setting, participants, & measurements: MEDLINE, EMBASE, and Renal Health Library were searched for relevant randomized clinical trials in adult CKD patients. Results were summarized using the random-effects model.Results: Eleven trials (991 patients) were included. In comparison to angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARB) plus placebo, nonselective AA along with ACEi and/or ARB significantly reduced 24 h proteinuria (seven trials, 372 patients, weighted mean difference [WMD] ؊0.80 g, 95% CI ؊1.27, ؊0.33) and BP. This did not translate into an improvement in GFR (WMD ؊0.70 ml/min/1.73m 2 , 95% CI ؊4.73, 3.34). There was a significant increase in the risk of hyperkalemia with the addition of nonselective AA to ACEi and/or ARB (relative risk 3.06, 95% CI 1.26, 7.41). In two trials, addition of selective AA to ACEi resulted in an additional reduction in 24 h proteinuria, without any impact on BP and renal function. Data on cardiovascular outcomes, long-term renal outcomes and mortality were not available in any of the trials.Conclusions: Aldosterone antagonists reduce proteinuria in CKD patients already on ACEis and ARBs but increase the risk of hyperkalemia. Long-term effects of these agents on renal outcomes, mortality, and safety need to be established. Clin J Am Soc Nephrol 4: 542-551, 2009. doi: 10.2215 C hronic kidney disease (CKD) affects 25 to 30 million Americans and several million people across the globe in both developed and developing nations (1,2). A number of treatment options have been shown to delay the progression of kidney damage (3,4). To date, the major impact on delaying the progression of CKD and the risk of end-stage kidney disease (ESKD) has been provided by the use of renin-angiotensin system (RAS) blockers such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor-blocking agents (ARB). These agents have become standard of care in proteinuric CKD patients (5-8). Both ACEi and ARB significantly reduce proteinuria and the risk of ESKD by about 20 to 30% (9). But this is suboptimal given the higher costs and burden of ESKD (10). Thus, studies exploring interventions for traditional and nontraditional risk factors for CKD are advocated (11).Animal studies have shown that aldosterone has an independent role in the development of hypertensive nephropathy and vascular injury resulting in myocardial and renal fibrosis, and its blockade reduces proteinuria (12-16). In humans, RAS blockade with ACEi or ARB results in an incomplete suppression of serum aldosterone levels, a phenomenon known as "aldosterone escape" (17). When patients are treated with ACEi or ARB, aldosterone levels decrease during...

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“…Примеча-тельно, что случаев гиперкалиемии в данном иссле-довании не отмечалось, что указывает на высокий уровень безопасности эпреленона [52]. Эти данные со-гласуются с результатами предыдущих исследований, которые указывают на низкую частоту гиперкалиемий у пациентов с ХБП [53][54][55][56][57][58][59]. Антипротеинемический эф-фект эплеренона, по всей видимости, является неза-висимым от антигипертензивного эффекта.…”

Section: эплеренон и протеинурияunclassified

A Selective Antagonist of Mineralocorticoid Receptor Eplerenone in Cardiology Practice

Gegenava

Драпкина

2015

Racionalʹnaâ farmakoterapiâ v kardiologii

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Несмотря на очевидность множества клинических исследований, по результатам которых [1][2][3] антагонисты рецепторов альдостерона получили I класс рекомен-даций к назначению (согласно American Heart Association/American College of Cardiology), в настоящее вре-мя эта группа препаратов в клинической практике ис-пользуется недостаточно часто. Согласно статистике в США эти препараты назначаются только 32% больных, для которых они могли бы быть актуальны [4,5]. Кро-ме того, недавние научные исследования, рассматри-ваемые далее, указали на более существенную взаи-мосвязь между гиперальдостеронизмом и сердечно-сосудистой патологией, нежели считалось ранее, что мо-жет увеличить спектр больных, которым могут назна-чаться антагонисты рецепторов альдостерона. Роль альдостерона в патологических процессах сердечно-сосудистой системыКак известно, гипоперфузия почек приводит к вы-свобождению ренина, который в свою очередь стиму-лирует секрецию альдостерона, повышающего внут-рисосудистый объем жидкости и преднагрузку на сердце. Тем не менее, при сердечной недостаточности причиной гипоперфузии является не сниженный объ-ем жидкости в организме, а уменьшение ударного объе-ма крови. Таким образом, компенсаторный механизм, который запускается в почках при сердечной недоста-точности, усиливает преднагрузку на и так перегруженное сердце. Исследования указывают на значительно более высокие уровни секреции альдостерона у пациентов с застойной сердечной недостаточностью в сравнении с нормой [6][7][8]. Хотя альдостерон и является ключевой частью системы поддержания электролитного и водно-солевого баланса, он, в то же время, достоверно ока-зывает повреждающее действие на сердечно-сосуди-стую систему. Так же, как и при избытке ангиотензина II, при избытке альдостерона наблюдается ухудшение ряда показателей, например повышение АД, гипер-трофия левого желудочка и фиброз миокарда [9][10][11][12]. Как известно, синтез альдостерона опосредован ан-гиотензином II. Рецепторы минералокортикоидов на-ходятся, в том числе, и в сердце, таким образом, аль-достерон также влияет и на пораженный миокард. Harda и соавт. продемонстрировали, что альдостерон вызывает усиление экспрессии мРНК ангиотензин-превращающего фермента (АПФ), что, в свою очередь, ведет к повышению уровня ангиотензина II [13]. По-рочный круг замкнулся: ангиотензин II усиливает вы-работку альдостерона, который в свою очередь приводит к увеличению образования ангиотензина II [14,15].В опытах на животных было продемонстрировано, что альдостерон в течение нескольких минут после кон-такта начинает воздействовать на миокард (так назы- The role of aldosterone in pathophysiological processes is considered. The effects of the selective antagonist of mineralocorticoid receptor eplerenone are analyzed. The advantages of eplerenone compared with spironolactone are discussed.

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Triple Pharmacological Blockade of the Renin-Angiotensin-Aldosterone System in Nondiabetic CKD: An Open-Label Crossover Randomized Controlled Trial

Cited by 92 publications

References 28 publications

Mechanisms and Treatment of CKD

Mechanisms and Treatment of CKD

Aldosterone Antagonists for Preventing the Progression of Chronic Kidney Disease

A Selective Antagonist of Mineralocorticoid Receptor Eplerenone in Cardiology Practice

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