Effects of dual blockade of the renin-angiotensin system in primary proteinuric nephropathies

Luño, José; Barrio, V.; Goicoechea, Maria; González, César; Vinuesa, Soledad García de; Gómez, Francisco Jiménez; Bernis, Carmen; Espinosa, Mario; Ahijado, F.; Gómez, José A.; P, Escalada

doi:10.1046/j.1523-1755.62.s82.10.x

Cited by 70 publications

(52 citation statements)

References 28 publications

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“…The most frequent adverse event has been hyperkalemia, which was managed easily with usual measures and only in rare instances was responsible for study dropout. As expected, this complication was more frequent in patients with reduced GFR (14,25). Some other adverse events, such as hypotension, cough, asthenia, and anemia, also have been reported.…”

Section: Combined Treatment With Acei and Arbsupporting

confidence: 73%

“…BP was reduced significantly from the first month until the end of follow-up for both systolic (SBP) and diastolic BP (DBP) compared with baseline but without any significant difference between groups at any time point. In this study, for the first time, it can be concluded that in chronic proteinuric nondiabetic nephropathies, dual blockade of the RAS with ACEI and ARB produces a beneficial antiproteinuric effect that is not attributable to more pronounced systemic BP reduction (25).…”

Section: Combined Treatment With Acei and Arbmentioning

confidence: 65%

“…We studied 45 patients who had primary proteinuric nephropathies (urinary protein/creatinine ratio 3.8 Ϯ 2.4 g/g) and normal or slightly reduced renal function (creatinine clearance 95 Ϯ 33 ml/min) and were enrolled in a 6-mo multicenter, prospective, open-label, randomized (1:1:1), active-controlled, and parallel trial (25). They received treatment with lisinopril (up to 40 mg/d), candesartan (up to 32 mg/d), and combination therapy at middle dosage (lisinopril up to 20 mg/d and candesartan up to 16 mg/d).…”

Section: Combined Treatment With Acei and Arbmentioning

confidence: 99%

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Dual Blockade of the Renin-Angiotensin System in the Progression of Renal Disease

Fernández-Juárez¹,

Barrio²,

Vinuesa³

et al. 2006

Journal of the American Society of Nephrology

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There is clear evidence that pharmacologic blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) reduces proteinuria and slows the progression of renal disease in diabetic and nondiabetic nephropathies, a beneficial effect that is not related to BP control. Some patients exhibit a significant beneficial response, whereas others do not. The absence of response may be explained by the incomplete blockade of the RAS obtained with ACEI. In the search of new alternatives that could improve the antiproteinuric and nephroprotective effects of RAS blockers, the association of ACEI and ARB might prove useful. ARB produces a complete blockade of the RAS. Several studies have shown a more marked antiproteinuric effect of the dual blockade of the RAS versus ACEI or ARB alone. A recent study also demonstrated that this more marked antiproteinuric effect is associated with less progression of renal disease in primary nondiabetic nephropathies despite a similar effect on BP. Until now, there has not been any reference to a beneficial effect on progression of the dual blockade in type 2 diabetic nephropathy, which is the most frequent cause of ESRD. A multicenter, prospective, open, active-controlled, and parallel-group trial was designed to compare the effects of an ACE inhibitor versus an ARB or its combination on renal disease progression, proteinuria, and cardiovascular events in type 2 diabetic nephropathy. S ingle-nephron hyperfiltration hypothesis, put forward by Brenner more than 20 yr ago, helped to explain the inexorable decline in renal function that is observed in chronic renal disease once the initial insult has disappeared. Angiotensin II is responsible for the increase in glomerular hydraulic capillary pressure by means of increasing systemic BP along with vasoconstriction of the efferent arteriole, thereby increasing filtration pressure in glomerular capillary walls. In experimental rat models with renal disease, a decrease of similar magnitude in systemic BP can be achieved either with angiotensin-converting enzyme inhibitors (ACEI) or with a combination of diuretics, reserpine and hydralazine, although only in those who are treated with ACEI is a reduction in glomerular capillary pressure and in progression of renal disease observed (1). J Am Soc NephrolBesides these hemodynamic changes, many other experimental models of renal damage that result in severe proteinuria (e.g., nephrosis by adriamycin or immune-complex glomerulonephritis [2,3]) have implicated angiotensin as a mediator in most of the inflammatory mechanisms that are involved in the progression of chronic renal disease. In proteinuric nephropathies, protein trafficking through proximal tubular cells, besides damaging this tubular segment, stimulates the production of NF-B, in part induced by angiotensin (4). NF-B is present in all cellular types and plays a crucial role in inflammation and apoptosis. In experimental models of nephritis, activation of NF-B results i...

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Section: Combined Treatment With Acei and Arbsupporting

confidence: 73%

Section: Combined Treatment With Acei and Arbmentioning

confidence: 65%

Section: Combined Treatment With Acei and Arbmentioning

confidence: 99%

See 1 more Smart Citation

Dual Blockade of the Renin-Angiotensin System in the Progression of Renal Disease

Fernández-Juárez¹,

Barrio²,

Vinuesa³

et al. 2006

Journal of the American Society of Nephrology

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“…In the previously mentioned study of nine patients with nondiabetic renal disease, dual RAS blockade (40 mg lisinopril ϩ 50 -150 mg losartan) induced a significantly greater reduction in proteinuria compared with monoblockade (37). Recently, the combination of ACEI and ARB has also been shown to produce beneficial antiproteinuric effects independent of blood pressure in 45 patients with primary nondiabetic nephropathies followed for 6 months in an open, randomized, paralleled study (44).…”

Section: Dual Ras Blockade Versus Maximal Ace Inhibitionmentioning

confidence: 99%

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

et al. 2003

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OBJECTIVE -We evaluated the renoprotective effects as reflected by short-term changes in albuminuria of dual blockade of the renin-angiotensin system (RAS) by adding an angiotensin II receptor blocker (ARB) to treatment with maximal recommended doses of an ACE inhibitor (ACEI) in patients with type 2 diabetes and nephropathy. RESEARCH DESIGN AND METHODS -A total of 20 patients (17 men and 3 women)with type 2 diabetes along with hypertension and nephropathy were enrolled in this doubleblind, randomized, two-period, crossover trial of 8 weeks of treatment with the ARB candesartan 16 mg daily and placebo added in random order to existing treatment with lisinopril/enalapril 40 mg daily or captopril 150 mg daily. At the end of each treatment period, we evaluated albuminuria in three 24-h urinary collections by turbidimetry, 24-h ambulatory blood pressure (ABP) using the Takeda-TM2420, and glomerular filtration rate (GFR) by the 51 Cr-EDTA plasmaclearance technique.RESULTS -During monoblockade of the RAS by ACEI treatment, albuminuria was 706 (349Ϫ1,219) mg/24 h [geometric mean (IQR)]; 24-h ABP was 138 Ϯ 3/72 Ϯ 2 mmHg (mean Ϯ SE); and GFR was 77 Ϯ 6 ml ⅐ min Ϫ1 ⅐ 1.73 m Ϫ2 (mean Ϯ SE). During dual blockade of the RAS by addition of candesartan 16 mg daily, there was a mean (95% CI) reduction in albuminuria of 28 (17Ϫ38) compared with ACEI alone (P Ͻ 0.001). There was a modest reduction in systolic/ diastolic 24-h ABP of 3/2 mmHg (Ϫ2 to 8 systolic, Ϫ2 to 5 diastolic; NS). Changes in albuminuria did not correlate to changes in ABP. Addition of candesartan 16 mg daily induced a small, insignificant decrease in GFR of 4 (Ϫ1 to 9) ml ⅐ min -1 ⅐ 1.73 m -2 .CONCLUSIONS -Dual blockade of the RAS provides superior short-term renoprotection independent of systemic blood pressure changes in comparison with maximally recommended doses of ACEI in patients with type 2 diabetes as well as nephropathy. Diabetes Care 26:2268 -2274, 2003D iabetic nephropathy occurs in 30 -40% of all diabetic patients and has become the leading cause of endstage renal disease in the western world (1). In diabetic patients, albuminuria independently predicts poor renal and cardiovascular outcome (1). Several clinical studies have clearly demonstrated that blockade of the renin-angiotensin system (RAS), either by an ACE inhibitor (ACEI) or an angiotensin II receptor blocker (ARB), reduces albuminuria, retards the progressive loss in renal function, and improves survival (2-7). The antiproteinuric response upon blockade of the RAS has been demonstrated to predict the subsequent long-term rate of decrease in glomerular filtration rate (GFR), i.e., the greater the initial decrease in albuminuria, the less the long-term decrease in kidney function (8,9). Consequently, the short-term reduction in albuminuria may serve to monitor treatment efficacy and long-term prognosis in diabetic nephropathy, and it has previously been advocated that albuminuria should be reduced as far as possible to obtain maximal renoprotective effects (10).Despite the proven benefit of ...

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“…Previously, one of the adverse effects of dual blockade therapy was considered to be hyperkalemia (25). However, the increase in serum potassium levels was thought to be a result of the progression of renal dysfunction, not a complication of add-on therapy.…”

Section: Discussionmentioning

confidence: 99%

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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Effects of dual blockade of the renin-angiotensin system in primary proteinuric nephropathies

Abstract: Dual blockade of the renin-angiotensin system with ACE inhibitors and AT1 receptor blockers produces a beneficial antiproteinuric effect that could not be explained only by the systemic blood pressure reduction. All treatments were well tolerated.

Cited by 70 publications

References 28 publications

Dual Blockade of the Renin-Angiotensin System in the Progression of Renal Disease

Dual Blockade of the Renin-Angiotensin System in the Progression of Renal Disease

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

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

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