Complementary effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in slowing the progression of chronic kidney disease

doi:10.1016/j.ahj.2009.04.008

American Heart Journal

Volume 157, Issue 6, Supplement, June 2009, Pages S7-S16

https://doi.org/10.1016/j.ahj.2009.04.008 Get rights and content

Chronic kidney disease (CKD) and end-stage renal disease continue to pose major healthcare challenges. Early initiation of therapy aimed at slowing the progression of CKD is essential. Increased renin-angiotensin-aldosterone-system activity and, in particular, elevated levels of angiotensin II (AII) play important roles in the development and progression of CKD. Therefore, pharmacologic therapies that block the effects of AII and reduce its pathogenic effects are cornerstones of clinical management. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been shown to have renoprotective effects in addition to their ability to control blood pressure. There is accumulating clinical evidence that the combination of an ACEI and an ARB provides greater renal protection, particularly in decreasing proteinuria, than does either agent alone.

Section snippets

RAAS and CKD

The RAAS is a critical link in the pathologic relationship between hypertension and renal disease. Regulation of extracellular fluid volume, sodium and water homeostasis, and electrolyte balance are primary functions of the RAAS. The sympathetic nervous system and vasoactive hormones (eg, endothelin, nitric oxide [NO], adenosine, and atrial natriuretic peptide) work with the RAAS to coordinate its hemodynamic effects and thereby maintain blood pressure (BP).

The cascade of peptide hormones that

Progression of renal dysfunction

There are many causes of renal dysfunction, including genetic abnormalities, autoimmune disease, toxic exposures, infections, and trauma, but hypertension and diabetes are among the most common causes.¹² Because the primary function of the kidney is to filter the blood, thereby, regulating blood volume and pressure and eliminating unwanted molecules while retaining essential ones, deterioration in renal function is reflected in the increasing inability of the kidney to filter the blood

Pharmacologic blockade of the RAAS

As has been detailed elsewhere in this supplement, ACEIs block the conversion of AI to AII, the peptide thought to initiate most of the deleterious effects of the RAAS. Because ACEIs also metabolize bradykinin, a direct vasodilator, and promote release of the vasodilators NO and prostacyclin, a second effect of ACEIs is the reduction of bradykinin degradation.³² However, studies have shown that levels of circulating AII return to pretreatment levels in patients receiving long-term ACEI therapy.

Guidelines

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative has prepared guidelines for the use of antihypertensive therapy, specifically for patients with diabetic kidney disease (with or without hypertension) or those with nondiabetic kidney disease with proteinuria.⁴ The recommended target BP for patients with diabetes is currently 130/80 mm Hg. In both situations, the guidelines call for initiation of therapy with either an ACEI or ARB. They further state that, at this time,

Summary

Key points when considering dual therapy are shown in Table I. Disruption of the RAS system, thereby, blocking the pathogenic effects of AII, is effective in slowing the onset and progression of CKD. Use of ACEIs and ARBs individually has been shown to decrease BP, reduce proteinuria, and slow progression of CKD. Therefore, the combination of an ACEI and ARB not only would block ACE-catalyzed production of AII and decrease metabolism of bradykinin but also antagonize the negative effects of AII

Disclosures

Editorial assistance was provided by Publication CONNEXION. This work was supported by Boehringer Ingelheim Pharmaceuticals Inc (Ingelheim, Germany).

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In diabetes, increased oxidative stress and impaired trace element metabolism play an important role in the pathogenesis of diabetic nephropathy. The objective of this research was to examine the outcomes of blocking the renin-angiotensin system, using either the angiotensin-converting enzyme inhibitor (ACEI), perindopril, or the angiotensin II type 1 (AT1) receptor blocker, irbesartan, on oxidative stress and trace element levels such as Zn, Mg, Cu, and Fe in the kidneys of diabetic rats that had been induced with streptozotocin.
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Biochemical analysis of the kidneys showed a distinct increase in oxidative stress, indicated by heightened levels of malondialdehyde (MDA) and decreased superoxide dismutase (SOD) activities, as well as reduced glutathione (GSH) levels in the kidneys of diabetic rats. In the kidneys of diabetic rats, the mean levels of Fe and Cu were found to be significantly higher than those of the control group. Additionally, the mean levels of Zn and Mg were significantly lower in the diabetic rats compared to the control rats. Both perindopril and irbesartan decreased significantly MDA content and increased SOD activities and GSH levels in the kidneys of rats with diabetes. The Zn and Mg concentrations in the kidneys of diabetic rats treated with perindopril and irbesartan were markedly higher than in untreated STZ-diabetic rats, while the Cu and Fe concentrations were significantly lower. The urinary excretion of rats treated with perindopril and irbesartan showed a pronounced increase in Cu levels, along with a significant reduction in Zn and Mg levels. Although diabetic rats demonstrated degenerative morphological alterations in their kidneys, both therapies also improved diabetes-induced histopathological modifications in the kidneys.
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Citation Excerpt :
CKD management can influence the rate of eGFR decline and mortality risk.7,40 For instance, multiple studies have shown that treatment with ACEi and ARB therapy can reduce proteinuria, lower blood pressure, and slow CKD progression.41,42 Consequently, the observed differences in baseline ACEi and ARB use, ranging from 25% to 75%, may have contributed to the differences in CKD progression.
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Renin-angiotensin-aldosterone-system blockade and contrast-induced nephropathy
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Complementary effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in slowing the progression of chronic kidney disease

Section snippets

RAAS and CKD

Progression of renal dysfunction

Pharmacologic blockade of the RAAS

Guidelines

Summary

Disclosures

Kidney Int

Lancet

Am J Kidney Dis

Am J Kidney Dis

Am J Kidney Dis

Am J Med

Immunopharmacology

J Biol Chem

Arch Biochem Biophys

J Biol Chem

Blood

Am J Kidney Dis

Kidney Int

Kidney Int

Lancet

Lancet

Lancet.

Am J Kidney Dis

Prevalence of chronic kidney disease in the United States

JAMA

2006 Annual data report: atlas of end stage renal disease in the United States

Predictors of early mortality among incident US hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS)

Clin J Am Soc Nephrol

Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI™) clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease

Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin

J Clin Invest

The renin-angiotensin system: physiology, pathophysiology, and pharmacology

Advan Physiol Educ

Effectively targeting the renin-angiotensin-aldosterone system in cardiovascular and renal disease: rationale for using angiotensin II receptor blockers in combination with angiotensin-converting enzyme inhibitors

J Renin Angiotensin Aldosterone Syst

Intrarenal angiotensin II generation and renal effects of AT1 receptor blockade

J Am Soc Nephrol

The role of hypertension in progression of chronic renal disease

Cardiorenal effects of the renin-angiotensin-aldosterone system

Hosp Physician

Pathophysiology of progressive nephropathies

N Engl J Med

Surrogate end points for clinical trials of kidney disease progression

Clin J Am Soc Nephrol

How does proteinuria cause progressive renal damage

J Am Soc Nephrol

Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data

Ann Intern Med

Glomerular preload and afterload reduction as a tool to lower urinary protein leakage: will such treatments also help to improve renal function outcome

J Am Soc Nephrol