Renoprotective Effects of Adding Angiotensin II Receptor Blocker to Maximal Recommended Doses of ACE Inhibitor in Diabetic Nephropathy

Rossing, Kasper; Jacobsen, Peter Karl; Pietraszek, Lotte; Parving, Hans‐Henrik

doi:10.2337/diacare.26.8.2268

Cited by 206 publications

(150 citation statements)

References 49 publications

(35 reference statements)

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“…These differential effects on serum potassium were related to a relatively smaller reduction in plasma aldosterone as a result of the ARB and were not related to changes in GFR. Also, another factor of independent blood pressure or albuminuria may contribute to these results as in other studies (27).…”

Section: Discussionsupporting

confidence: 62%

Add-On Angiotensin Receptor Blocker in Patients Who Have Proteinuric Chronic Kidney Diseases and Are Treated with Angiotensin-Converting Enzyme Inhibitors

Kanno

Takenaka

Nakamura

et al. 2006

Clinical Journal of the American Society of Nephrology

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The benefit of the add-on angiotensin II receptor blocker candesartan to angiotensin-converting enzyme (ACE) inhibitors in inhibition of progression of nephropathy in hypertensive patient with nondiabetic renal disease compared with monotherapy with ACE inhibitors remains controversial. All patients were previously treated with ACE inhibitors. Urinary protein excretion of patients exceeded 1.0 g/d despite treatment with ACE inhibitors. Ninety hypertensive patients with chronic renal insufficiency were randomly assigned to one of two groups. One group received ACE inhibitor plus candesartan (2 to 12 mg/d), and a control group received only ACE inhibitor. The target BP was <130/80 mmHg. The primary outcome was the changes in serum creatinine and the reduction of proteinuria. The mean duration of follow-up was 3.1 ؎ 0.4 yr. At years 2 and 3, systolic and diastolic BP were reduced from 140 ؎ 3/84 ؎ 2 to 129 ؎ 1/78 ؎ 2 mmHg (candesartan group) and from 135 ؎ 2/85 ؎ 2 to 130 ؎ 2/80 ؎ 2 mmHg (ACE inhibitors group). In both groups, both systolic and diastolic BP decreased significantly from the beginning to the end of the study (P < 0.01). The serum creatinine concentration increased from 3.02 ؎ 0.27 to 3.38 ؎ 0.49 mg/dl (candesartan plus ACE inhibitor group) versus 3.00 ؎ 0.37 to 4.48 ؎ 0.57 mg/dl (ACE inhibitor group; P < 0.01) at year 3. Although the level of proteinuria significantly declined in each group (P < 0.05), the degree of reductions in proteinuria was greater in the candesartan group than in the ACE inhibitors group (P < 0.01). In the patients who were treated with candesartan and ACE inhibitor or ACE inhibitor alone, pretreatment proteinuria correlated significantly with decline of renal function, whereas reduction of proteinuria negatively correlated with decline in renal function in the patients who were treated with candesartan. Candesartan with an ACE inhibitor is effective in slowing the progression of renal insufficiency in hypertensive patients with nondiabetic renal disease through reduction of proteinuria.Clin T he Ramipril Efficacy in Nephropathy (REIN) study was designed to evaluate the renal effects of the angiotensin-converting enzyme (ACE) inhibitor ramipril on proteinuric nondiabetic chronic nephropathies (1). In this study, the incidence of ESRD was reduced by 33, 37, and 100% in the lowest, middle, and highest trisects of the patients, respectively, compared with conventional antihypertensive treatment. In general, patients with proteinuria of Ն2 g protein/24 h showed faster progression than patients who excreted Ͻ2 g/24 h urinary protein (2). The former group of patients benefited the most from ramipril treatment. Thus, ACE inhibition consistently slowed GFR decline and progression to ESRD within each trisect of basal GFR (3,4). These analyses show that the renoprotective effect of the renin-angiotensin system (RAS) inhibitors is independent of the severity of renal failure and suggest that these drugs would benefit all patients with proteinuric chronic nephropathies (5). Besides ACE inh...

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Section: Discussionsupporting

confidence: 62%

Add-On Angiotensin Receptor Blocker in Patients Who Have Proteinuric Chronic Kidney Diseases and Are Treated with Angiotensin-Converting Enzyme Inhibitors

Kanno

Takenaka

Nakamura

et al. 2006

Clinical Journal of the American Society of Nephrology

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“…A sample-size calculation showed a necessary minimum of 16 patients to detect a 25% change in urinary albumin excretion rate when based on three 24-h urinary collections (␣ ϭ 0.05, ␤ ϭ 0.80), as described in detail previously (18). Normally distributed variables are expressed as means and changes upon treatment as mean difference with 95% CIs.…”

Section: Statisticsmentioning

confidence: 99%

Beneficial Effects of Adding Spironolactone to Recommended Antihypertensive Treatment in Diabetic Nephropathy

et al. 2005

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OBJECTIVE -The objective of this study was to evaluate the safety and short-term effect of adding spironolactone to conventional antihypertensive treatment including diuretics and maximally recommended doses of an ACE inhibitor or an angiotensin II receptor blocker (ARB) on albuminuria and blood pressure in type 2 diabetic patients with nephropathy.RESEARCH DESIGN AND METHODS -Twenty-one type 2 diabetic patients with nephropathy were enrolled in a randomized, double-masked, cross-over study. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for 8 weeks, respectively, in addition to ongoing antihypertensive treatment including diuretics and maximally recommended doses of an ACE inhibitor and/or an ARB. At the end of each treatment period, albuminuria, 24-h ambulatory blood pressure (ABP), and glomerular filtration rate (GFR) were determined.RESULTS -During the addition of placebo, values were as follows: albuminuria (geometric mean [range]) 1,566 762] mg/24 h, ABP (mean Ϯ SE) 138 Ϯ 3/71 Ϯ 1 mmHg, and GFR (mean Ϯ SE) 74 Ϯ 6 ml/min per 1.73 m 2 . During the addition of spironolactone, albuminuria was reduced by 33% (95% CI 25-41) (P Ͻ 0.001), fractional clearance of albumin by 40% (24 -53) (P Ͻ 0.001), and 24-h ABP by 6 mmHg (2-10) for systolic and 4 mmHg (2-6) for diastolic (P Ͻ 0.001 for both). The change in albuminuria did not correlate with the change in systolic 24-h ABP (r ϭ 0.19, P ϭ 0.42) or diastolic 24-h ABP (r ϭ 0.01, P ϭ 0.96). Spironolactone treatment induced an insignificant reversible reduction in GFR of 3 ml/min per 1.73 m 2 (Ϫ0.3 to 6) (P ϭ 0.08). One patient was excluded from the study due to hyperkalemia. Otherwise treatment was well tolerated.CONCLUSIONS -Our study suggests that spironolactone safely adds to the reno-and cardiovascular protective benefits of treatment with maximally recommended doses of ACE inhibitor and ARB by reducing albuminuria and blood pressure in type 2 diabetic patients with nephropathy. Diabetes Care 28:2106 -2112, 2005A ldosterone, the end product of the renin-angiotensin-aldosterone system (RAAS), has attracted renewed attention as an important mediator of both cardiovascular and renal disease (1,2). Accumulating experimental evidence suggests that circulating aldosterone per se contributes directly to renal and cardiovascular disease by inducing inflammation, fibrosis, and necrosis in end-organ tissues such as the heart, brain, and kidney (3). Moreover, aldosterone blockade has been shown to greatly improve survival in patients with chronic heart failure (4,5).Angiotensin II has long been considered the main mediator of the pathophysiological effects of the RAAS, and in diabetic nephropathy the renoprotective effects of treatment with an ACE inhibitor or an angiotensin receptor blocker (ARB) are well established (6 -9). Both ACE inhibitor and ARB treatments initially suppress plasma aldosterone. Eventually, however, plasma aldosterone may return to pretreatment levels, i.e., the aldosterone escape phenomenon. Aldosterone e...

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“…All strategies reduce proteinuria compared with single-agent therapy (5)(6)(7)(8)(9)(10)(11), but hyperkalemia is a risk (12,13). Regimens including an ACE inhibitor and ARB or either drug and DRI are not recommended not only because of the risk of hyperkalemia but also because of renal failure and hypotension, which were seen in large clinical trials (14,15).…”

Section: Introductionmentioning

confidence: 99%

Potassium Handling with Dual Renin-Angiotensin System Inhibition in Diabetic Nephropathy

Buren

Adams‐Huet

Nguyen³

et al. 2014

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are the cornerstones of pharmacologic therapy in diabetic nephropathy. Mineralocorticoid receptor blockers reduce proteinuria as single agents or add-on therapy to other renin-angiotensin-aldosterone system-inhibiting drugs in these patients. The long-term benefits and ultimate role of mineralocorticoid receptor blockers in diabetic nephropathy remain unknown. A clinical trial previously showed that the kalemic effect of spironolactone is higher than losartan when added to lisinopril in patients with diabetic nephropathy. The purpose of this study was to investigate if renal potassium handling was primarily responsible for that observation.Design, setting, participants, & measurements In a blinded, randomized, three-arm placebo-controlled clinical trial, 80 participants with diabetic nephropathy taking lisinopril (80 mg) were randomized to spironolactone (25 mg daily), losartan (100 mg daily), or placebo (trial dates from July of 2003 to December of 2006). Serum potassium, aldosterone, and 24-hour urine sodium, potassium, and creatinine were measured over 48 weeks. Differences were analyzed with repeated measures mixed models.Results Mean follow-up serum potassium was 5.0 mEq/L for spironolactone, 4.7 mEq/L for losartan (P=0.05 versus spironolactone), and 4.5 mEq/L for placebo (P,0.001 versus spironolactone; P=0.03 versus losartan). The difference in serum potassium was 0.23 mEq/L for losartan versus placebo (P=0.02), 0.43 mEq/L for spironolactone versus placebo (P,0.001), and 0.2 mEq/L for spironolactone versus losartan (P=0.05). Serum and urine potassium excretion and secretion rates were similar between groups throughout the study.Conclusion Spironolactone raised serum potassium more than losartan in patients with diabetic nephropathy receiving lisinopril, despite similar renal sodium and potassium excretion. This finding suggests that extrarenal potassium homeostasis contributes to hyperkalemia in these patients. A better understanding of extrarenal potassium homeostasis will provide an opportunity to use this drug more safely in patients with diabetic nephropathy as well as other patient populations.

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Renoprotective Effects of Adding Angiotensin II Receptor Blocker to Maximal Recommended Doses of ACE Inhibitor in Diabetic Nephropathy

Cited by 206 publications

References 49 publications

Add-On Angiotensin Receptor Blocker in Patients Who Have Proteinuric Chronic Kidney Diseases and Are Treated with Angiotensin-Converting Enzyme Inhibitors

Add-On Angiotensin Receptor Blocker in Patients Who Have Proteinuric Chronic Kidney Diseases and Are Treated with Angiotensin-Converting Enzyme Inhibitors

Beneficial Effects of Adding Spironolactone to Recommended Antihypertensive Treatment in Diabetic Nephropathy

Potassium Handling with Dual Renin-Angiotensin System Inhibition in Diabetic Nephropathy

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