Reduction of proteinuria with angiotensin
receptor blockers
Jan Galle
INTRODUCTION
Proteinuria is an early and sensitive marker for progressive renal dysfunction.1 In the early stages of kidney disease, very small amounts of protein are detectable in the urine (microalbuminuria). As the disease progresses to clinical or overt nephrop-athy, larger quantities of urinary protein can be measured (macroalbuminuria). Hemodynamic injury to the vascular endothelium and glomerulus can be induced by both systemic and glomerular hypertension, which is promoted by an activated renin–angiotensin system (RAS). Angiotensin II, the primary agent of this system, is centrally involved in all stages of renal pathophysiology.2
Angiotensin-II-receptor blockers (ARBs) are primarily prescribed as antihypertensive drugs, and several guidelines recommend these agents as first-line therapy for patients with arterial hyper-tension.3–5 The benefits of ARBs extend, however, beyond lowering of blood pressure. Their use to selectively inhibit the angiotensin II type 1 (AT1) receptor can protect against the progression of kidney disease.
This article addresses the central role of angio-tensin II in the risk, development and progres-sion of cardiovascular and renovascular disease and considers the potential of RAS blockade for preventing target-organ damage in patients with diabetic nephropathy. It also summarizes the findings from several trials, addressing the efficacy of ARB therapy (specifically with telmis-artan) in comparison with that for an angio-tensin-converting-enzyme (ACE) inhibition with enalapril, another ARB (valsartan), and conventional treatment in patients with and without hypertension.
This information was first presented at a meeting sponsored by Boehringer Ingelheim and held in Lisbon on 28 and 29 April, 2006. The meeting, which addressed a range of topics related to RAS blockade, was endorsed by the European Society of Hypertension and the International Society of Nephrology. The meeting was called A
new dawn in cardiovascular protection: total cardio-vascular risk: rigorous treatment of risk factors. Renal pathophysiology is elicited by activation of angiotensin II type 1
(AT1) receptors at all stages of renovascular disease. Angiotensin receptor blockers (ARBs) that specifically block the AT1 receptor offer the potential to prevent or delay progression to end-stage renal disease independently of reductions in blood pressure. Proteinuria—an early and sensitive marker for progressive renal dysfunction—is reduced by ARB use in patients with type 2 diabetic nephropathy and microalbuminuria or macroalbuminuria. Retrospective analysis of data available from early trials has confirmed this finding, and has shown that albuminuria reduction is associated with lessening of cardiovascular risk. The ARB telmisartan is equivalent to enalapril in preventing glomerular filtration rate decline, and equivalent to valsartan in reducing proteinuria. Telmisartan is more effective than conventional therapy in lowering the risk of transition to overt nephropathy in hypertensive and normotensive patients. An additive effect has been seen in smaller studies when telmisartan has been added to lisinopril therapy, and high-dose telmisartan reduces albuminuria better than low-dose telmisartan. Similar data were obtained with other ARBs such as candesartan, losartan, valsartan, or irbesartan. These data support the proposition that blockade of the renin–angiotensin system in beyond that required for maximum blood pressure reduction provides optimum renal protection.
KEYWORDS angiotensin receptor blockers, diabetes, proteinuria, renal disease, renin–angiotensin system blockade
J Galle is Head of the Department of Nephrology and Dialysis at the Klinikum Lüdenscheid, and a Fellow of the Deutsche Gesellschaft für Kardiologie, Herz, und Kreislaufforschung and the Deutsche Herzstiftung, Lüdenscheid, Germany.
Correspondence
Direktor der Klinik für Nephrologie, Klinikum Lüdenscheid, Paulmannshöher Strasse 14, D-58515 Lüdenscheid, Germany
Received 23 November 2006 Accepted 2 January 2007
www.nature.com/clinicalpractice doi:10.1038/ncpcardio0806
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ANGIOTENSIN II IN RENOVASCULAR AND CARDIOVASCULAR DISEASE
Renal disease and coronary artery disease both develop through a general progression of pathophysiological events, beginning with cardiovascular risk factors and culminating with end-organ disease.6 Risk factors such as high blood pressure, raised concentrations of cholesterol, diabetes mellitus, and insulin resis-tance elicit pathological changes in the heart and vasculature. Changes include atheroscle-rosis, left ventricular hypertrophy, coronary vascular obstruction, and myocardial ischemia. Patients can go on to experience myocardial infarction and arrhythmia, which can lead to sudden death. In patients who survive, ventric-ular wall remodeling eventually occurs, leading to increased muscle mass and cardiac dilatation, ultimately resulting in congestive heart failure. In renovascular disease, the same cardiovas-cular risk factors elicit pathological changes, such as endothelial dysfunction and microal-buminuria. These changes can lead to increased risk of coronary heart disease and nephrotic syndrome, reduced glomerular filtration rate (GFR), and nephrosclerosis. Eventually, end-organ damage occurs in the form of chronic kidney disease stage V.
Angiotensin II is centrally involved in target-organ damage at every stage of cardiovas-cular and renal pathophysiologies. Figure 1 illustrates the roles of angiotensin II in renal
disease.2 The major biological actions of angio-tensin II in the kidney are mediated by two functionally distinct receptors, AT1 and AT2.2 Activation of AT1 receptors is responsible for the pathophysiological effects of angiotensin II, whereas activation of AT2 receptors plays a part in opposing these pathophysiological effects.7 AT1 receptors are abundant in the efferent arte-rioles of each nephron of the kidney. Receptor activation by angiotensin II induces vasocon-striction, which raises glomerular capillary pressure and increases glomerular filtration, and leads to proteinuria. In addition to renal vasoconstriction induced by angiotensin II, direct profibrotic and proinflammatory actions of angiotensin II and aldosterone can promote kidney damage, seen as, for example, activation of plasminogen activator inhibitor 1 or trans-forming growth factor β (Figure 1).2
BLOCKING THE RAS TO PREVENT TARGET-ORGAN DAMAGE
Potential of ARBs versus ACE inhibitors
Angiotensin II is a central mediator of hemody-namic and nonhemodyhemody-namic processes of renal injury. Use of antihypertensive agents that block the RAS will, therefore, cause vasodilatation of the efferent arterioles in addition to lowering blood pressure. These actions should reduce intraglomerular pressure, thereby lessening proteinuria and providing renoprotective effects in patients with nephropathy. Although ACE inhibitors and ARBs both target the RAS, they do so in different ways. This difference might affect their potential benefits in end-organ protection. ACE inhibitors reduce blood pres-sure by blocking the conversion of angiotensin I to angiotensin II, as well as by preventing the breakdown of bradykinin and other vaso-active peptides. Other enzymatic pathways can, however, also lead to the generation of angio-tensin II. Over time, therefore, these pathways might compensate for the effect of ACE inhibi-tion, leading to a gradual return of angiotensin II to baseline levels. This phenomenon is known as angiotensin II escape.8,9 By contrast, ARBs
specifically block the AT1 receptor, thereby effectively inhibiting the pathophysiological effects of angiotensin II. This action offers the potential for additional benefit beyond blood pressure reduction, including reduced protein-uria and the progression to end-stage renal disease (ESRD) in patients with type 2 diabetes and nephropathy.
Figure 1 The central role of angiotensin II in the pathophysiology of renal
disease. Permission obtained from Lippincott, Williams & Wilkins © Brewster UC and Perazella MA (2004) Am J Med 116: 263–272. Abbreviations: PAI-1, plasminogen activator inhibitor 1; TGF-β, transforming growth factor β.
Extracellular matrix Adhesion molecules Chemotactic factors Macrophage infiltration TGF-β PAI-1 ■ Glomerular pressure injury
■ Oxidative stress ■ Proteinuria ■ Nuclear factor-κB activation ■ Hyperfiltration ■ Glomerular capillary hypertension ■ Glomerular sclerosis ■ Tubulointerstitial fibrosis Chronic kidney disease Reduction in nephron mass Angiotensin II Cell proliferation Collagen deposition Apoptosis NSIN II IN REN NSIN II IN R OVASC OVA
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gy of renal y of renal Wilkins © Brewstens © Brewst 72. Abbreviations: PAI-1,. Abbreviations: PAI-1 nsforming growth factor sforming growth factor ββ.UNCORRECTED
ULAR LAR DISEASEISEASE
coronary artery disease coronary artery disease through a general progression ough a general progression ophysiological events, beginning wphysiological events, beginning ardiovascular risk factors and curdiovascular risk factors and cu with end-organ disease.
with end-organ disease.66Risk high blood pressure, ra high blood pressure cholesterol, diabe cholesterol, diabe tance elicit tance eli and matory a matory sterone can promterone can pro as, for example, activat as, for example, activa en activator inhibitor 1 or trann activator inhibitor 1 or tr g growth factor growth factor ββ (Figure 1).(Figure 1).22
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PROOF
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Clinical trials assessing reductions in proteinuria and progression to ESRD
ACE inhibitors and ARBs have been chosen for study in numerous clinical trials.10 ACE inhibi-tors have been investigated in patients with type 1 or type 2 diabetes.11–14 Overall, studies of these drugs in type 2 diabetes have provided no convincing evidence of efficacy beyond blood pressure control.15
ARBs have been shown to reduce the inci-dence of hard endpoints (i.e. relate directly to renal function), such as doubling of baseline serum creatinine concentration or develop-ment of ESRD. The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study16,17 included 1,513 patients with type 2 diabetes and nephropathy. The risk of developing these two hard endpoints was reduced by 25% and 28%, respectively, when compared with placebo.16 Reduced progression of renal disease was seen in all three tertiles of baseline serum creatinine concentration.17 In the Irbesartan Diabetic Nephropathy Trial (IDNT),18 a total of 1,715 hypertensive patients with type 2 diabetes and urinary protein excre-tion of at least 900 mg/day were randomly assigned 300 mg irbesartan, 10 mg amlo-dipine, or placebo daily for a mean duration of 2.6 years. The risk of the primary composite endpoint (doubling of serum creatinine, devel-opment of ESRD, or death) was reduced in the
ARB-treated patients by 20% compared with placebo (P = 0.02) and by 23% compared with amlodipine group (P = 0.006). In both RENAAL and IDNT, the superiority of ARB therapy was evident despite very similar changes in blood pressure in the comparator groups.
As early as 2002, the results from these and other trials (Table 1) motivated the American Diabetes Association to recommend that use of ARBs should be standard in the treatment of diabetic nephropathy in patients with type 2 diabetes.19 Evidence that has become avail-able since that guideline was published has strengthened the case, and the Association’s position has been reiterated.20 For example, a post hoc subanalysis of the IDNT trial provided strong evidence of the blood-pressure-inde-pendent effects of irbesartan compared with amlodipine.21 Figure 2 shows the relative risk of a renal endpoint in relation to systolic blood pressure and treatment (irbesartan, amlodipine, or placebo). In each treatment group, falls in systolic blood pressure during follow-up were associated with an reduced risk of reaching a renal endpoint. However, in all quartiles of systolic blood pressure, ARB-treated patients experienced improved renal outcomes compared with patients receiving amlodipine or placebo. The relative risk of a renal endpoint in patients taking amlodipine was similar to that in placebo-treated patients. Placebo was, however, Table 1 Summary of important trials investigating the renoprotective effects of angiotensin-receptor blockers.
Study Duration Drug Primary endpoint Systolic/diastolic blood
pressure (mmHg)
Proteinuria
(% change from baseline)
Patients with type 2 diabetes and microalbuminuria IRMA II26 (n = 590) 2 years Irbesartan 150 mg, irbesartan 300 mg or placebo Microalbuminuria –10/–7; –12/–7; –9/–7 –24%; –38%; –2% MARVAL27 (n = 332) 24 weeks Valsartan 80–160 mg or amlodipine 5–10 mg Microalbuminuria –11/–7; –12/–7 –44%; –8%
Patients with type 2 diabetes and macroproteinuria or reduced GFR RENAAL16 (n = 1,513) 3.4 years Losartan 50–100 mg or placebo Death, doubling of creatinine, or need for dialysis or renal transplantation –12/–8; –11/–8 –35%; 18% IDNT21 (n = 1,715) 2.6 years Irbesartan 300 mg, amlodipine 10 mg, or placebo Death, doubling of creatinine, or need for dialysis or renal transplantation
–20/–10; –18/–10; –14/–7 –33%; –6%; –10%
Abbreviations: GFR, glomerular filtration rate; IDNT, Irbesartan Diabetic Nephropathy Trial; IRMA II, IRbesartan in patients with type 2 diabetes and MicroalbuminuriA; MARVAL, MicroAlbuminuria Reduction with VALsartan; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan.
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sen for for ACE ACE inhibi-in patients with type in patients with type s. 1–14–14 Overall, studies oOverall, studies of type 2 diabetes have provided no pe 2 diabetes have provided n cing evidence of efficacy beyond bing evidence of efficacy beyond b ressure control.
ressure control.1515
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nal function), nal function),
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PROOF
the inci-he inci-ectly to ectly to aseline aseline elop-i t i pared pared In both RENboth REN rity of ARB therapy wity of ARB therapy very similar changes in bloosimilar changes in n the comparator groups.the comparator groups
s early as 2002, the results from thy as 2002, the results from t other trials (Table 1) motivated other trials (Table 1) motivated Diabetes Association to r Diabetes Association of ARBs should be of ARBs should be of diabetic n of diabetic n 2 diabediab
administered on a background of standard antihypertensive therapy with drugs other than calcium-channel blockers or RAS inhibitors.
As well as hard endpoints, ARBs have been extensively investigated in relation to so-called soft endpoints, especially proteinuria. Although this disorder does not directly cause death or disability, it is a key marker of various underlying pathophysiologies and is linked to decline in renal function,22 systemic endothe-lial dysfunction,23 target-organ damage,24 and cardiovascular mortality.25 ARBs have effec-tively reduced urinary protein concentrations in patients with type 2 diabetic nephropathy, independently of blood pressure lowering. These drugs act either by reducing microalbuminuria in early-stage kidney disease or macroalbumin-uria in later-stage disease when GFR is already reduced (Table 1).16,21,26,27 Overall, reductions in proteinuria seen with ARB treatment have been reported as greater than those with placebo or the calcium-channel blocker amlodipine, despite similar blood pressure reductions in the ARB and calcium-channel blocker groups.
Albuminuria can be employed in risk stratifi-cation and treatment assessment. In a post hoc analysis of the LIFE study, decreased microalbu-minuria after ARB treatment translated into a reduction in cardiovascular events in hyperten-sive patients without overt renal disease.28 The primary analysis of the LIFE study29
demon-strated that, in 9,193 patients with hyperten-sion and left ventricular hypertrophy, the risk of the primary composite endpoint over 4 years (death, myocardial infarction, or stroke) was significantly lower among patients receiving the ARB losartan than among those taking the β -blocker atenolol, despite similar blood pressure reductions in both groups (23.8 versus 27.9 inci-dences per 1,000 patient-years, P = 0.021). In the post hoc analysis, the incidence of the primary composite endpoint was assessed in 8,206 patients according to four levels of baseline and in-treatment values of urinary albumin-to-creat-inine ratio (≤0.5, 0.5–1.0, 1.0–3.0, and >3.0 mg/ mmol).30 Albuminuria concentrations during therapy were closely associated with the risk of developing the primary composite endpoint. When urinary albumin-to-creatinine ratio decreased during treatment, with values moving from the lowest to the highest stratum, the risk for a cardiovascular endpoint increased by three-fold to fourthree-fold. This observation, which was independent of blood-pressure-lowering effects, strongly suggests that treatment-induced reduc-tions in albuminuria lead to decreased cardio-vascular risk. The distribution of patients across the urinary albumin-to-creatinine ratio strata changed during the study: at baseline, the ratio for 43% of patients was less than 1 mg/mmol, but at 4 years the equivalent value was seen in 53%. Response to treatment was marked by move-ment of patients’ ratio values into a stratum that was associated with reduced cardiovascular risk. Monitoring of albuminuria could, therefore, be an important part of the management of hyper-tensive patients with albuminuria. Intensification of antihypertensive treatment might be consid-ered to reduce urinary protein in patients with ratios in the highest-risk strata.
The importance of minimizing the progres-sion of albuminuria in patients with type 2 diabetes poses the question of whether ARBs should be considered for all such patients, whether they have hypertension or not. Only one major study has thus far assessed an ARB in this role: The INcipieNt to OVert—Angiotensin II receptor blocker, Telmisartan, Investigation On type II diabetic Nephropathy (INNOVATION) study.31 The results of this study have not yet been published.
Choice of intervention for RAS blockade
Although ARBs and ACE inhibitors are now established as the therapies of choice for Figure 2 The close relationship between systolic blood pressure and the risk
of renal endpoint in the Irbesartan Diabetic Nephropathy Trial subanalysis. Permission obtained from the American Society of Nephrology © Pohl MA et al. (2005) J Am Soc Nephrol 16: 3027–3037. Abbreviation: SBP, systolic blood pressure. Relative risk of r enal endpoint Am iodipine Placeb o Irbesartan <134 134–140 141–149 >149 Quartile of mean SBP ( mmHg) Treatm ent 0.600 1.200 1.800
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ood pressure and the riskod pressure and the ris ephropathy Trial subanalysis. phropathy Trial subanalys Society of Nephrology © Pohl MA Society of Nephrology © Pohl M et –3037. Abbreviation: SBP, systolic –3037. Abbreviation: SBP, systol
UNCORRECTED
round of standardound of standard rapy with drugs other thanapy with drugs other than el blockers or RAS inhibitors.blockers or RAS inhibitors. ll as hard endpoints, ARBs have bas hard endpoints, ARBs have xtensively investigated in relatiotensively investigated in relati called soft endpoints, especi called soft endpoints, esp Although this disorder Although this disord death or disabilit death or disabilit underlying underlyi decli ations d ations ated with the ris ated with the ri mary composite endpoi mary composite endp ry albumin-to-creatinine raty albumin-to-creatinine r ed during treatment, with values mod during treatment, with values m rom the lowest to the highest stratuom the lowest to the highest stratu for a cardiovascular endpoint i for a cardiovascular endpoint fold to fourfold. This fold to fourfold. Th independent of b independen strongly su strongly su tion tio
PROOF
so-roteinuria.oteinuria ot directly causerectly cause a key marker of variouskey marker of various physiologies and is linked to physiologies and is linked to nal function,nal function,2222 systemic endothe systemic endothe on,
on,2323 target-organ damagtarget-organ damage mortality. mortali 255 ARBAR rinary pro rinar yp
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umm ular risk. Thear risk. Th the urinary album the urinary album changed during the changed during for 43% of patients w3% of patie at 4 years the at 4 years the Respon Responpatients with diabetic nephropathy, much research remains to be done. A key question is whether one of these drug classes should be the preferred over the other. Only one study, the Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) study, has so far attempted to address this issue.32
DETAIL was a 5-year, prospective, multi-center, randomized, double-blind study done in 250 patients with type 2 diabetes and mild to moderate hypertension (seated diastolic/systolic blood pressure during therapy ≤95/180 mmHg), a urinary albumin excretion rate higher than 10 μg/min and lower than 1,000 μg/min, and normal or only mildly impaired GFR [Author: Correct?] (≥70 ml/min/1.73 m2). Telmisartan has the longest plasma half-life and highest volume of distribution of all agents in the ARB class.30 In patients with type 2 diabetes at the earliest stage of renal disease this drug can improve renal endothelial function.33 Enalapril had previously been shown in a 6-year study to significantly reduce the decline of renal function in patients with type 2 diabetes and microalbuminuria.34 Eligible patients received forced titration with either 40–80 mg telmis-artan or 10–20 mg enalapril, with optional dose reduction to 40 mg or 10 mg, respectively. The primary endpoint was change in GFR, measured by the iohexol method, after 5 years of treatment. The two treatments produced similar reductions in blood pressure. The GFR at 5 years was reduced to a similar degree by telmisartan or enalapril therapy (Figure 3), and the rate of decline reduced progressively during the study.31 The typical annual rate of GFR
decline in untreated diabetics with proteinuria is 10–12 ml/min/1.73 m2.35
By year 3 of the DETAIL study, the annual decline in GFR had stabilized to approximately 2 ml/min/1.73 m2, which is similar to the age-related decline expected in healthy individuals.36 Interestingly, the mortality in DETAIL was unexpectedly low given the link between renal and cardiovascular disease. Only six patients died in each treatment group, which represented about 5% of the study population. By contrast, the expected mortality rate in older patients with type 2 diabetes of more than 5 years’ dura-tion [Author: Correct?] is around 35% in those with microalbuminuria and 50% in those with macroalbuminuria.37
The GFR-preserving effect provided by telmisartan in the DETAIL study may be
compared with that of other ARBs in studies of renal disease progression, although the popu-lations and treatment durations differ between studies.38 In DETAIL, the mean yearly decline in measured GFR was 3.7 ml/min/1.73 m2 after 5 years of treatment with 40–80 mg telmis-artan.32 In RENAAL, the yearly decline in estimated GFR was 4.4 ml/min/1.73 m2 after 3.4 years of treatment with 100 mg losartan.16 In the IRbesartan in patients with type 2 diabetes and MicroalbuminuriA (IRMA 2) study,21 the corresponding value was –5.7 ml/ min/1.73 m2 after 2 years of treatment with 300 mg irbesartan,21 and in IDNT it was –5.5 ml/min/1.73 m2 after 2.6 years of treatment with the same dose.26
A comparison of the antiproteinuric effects of different ARBs has been investigated in only one large study, a trial to inVestigate the efficacy of telmIsartan versus VALsartan in hypertensive type-2 DIabetic patients with overt nephropathy (VIVALDI).39 This study was a prospective, 1-year, multicenter, randomized, double-blind, parallel-group trial of patients with type 2 diabetes, hypertension (seated systolic/diastolic blood pressure >130/>80 mmHg), macroalbu-minuria (≥900 mg/day) and serum creatinine 97–265 μmol/l in women and 115–265 μmol/l in men. Patients were randomized to receive 80 mg
Figure 3 Changes from baseline in glomerular filtration rate with telmisartan
versus enalapril in the DETAIL study. Permission obtained from Cambridge Medical Publications © Makino H et al. (2005) J Int Med Res 33: 677–686.
Change in glo
m
erular filtration rate
( m l/ m in/1.73 m 2) 10 – 5 – 0 – –5 – –10 – –15 – –20 – –25 – 0 1 2 Time (years)
Number of patients at risk (total number [number carried forward]) Enalapril Telmisartan 103 (0) 86 (0) 110 (22) 99 (23) 113 (23) 102 (21) 113 (40) 102 (31) 113 (39) 103 (41) 3 4 5 Enalapril Telmisartan
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telmis- mis-with optional th optional r 10 mg, respectively. r 10 mg, respectively. oint was change in GFR, t was change in GFR the iohexol method, after 5 years iohexol method, after 5 year tment. The two treatments prodment. The two treatments prod imilar reductions in blood pressuremilar reductions in blood pressu at 5 years was reduced to a s at 5 years was reduced t telmisartan or enalapril telmisartan or enalapri he rate of declin he rate of declin study. study33compared with that of compared with that of renal disease pro renal disease pr lations anions an stud s
aseline in glomerular filtration rate weline in glomerular filtration rate w he DETAIL study. Permission obtaine he DETAIL study. Permission obtain cations © Makino Hations © Makino et alal. (2005) . (2005) J InJ In
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r carried forwar (23) 113 (23) 102 (21) 113 (40 102 (31) 113 10 4PROOF
GFR GFR egree by egree by 3), and 3), and during during GFR GFR iARBs in studiBs in stud on, although the pop on, although the po ment durations differ betweedurations differ b In DETAIL, the mean yearly declinn DETAIL, the mean yearly d easured GFR was 3.7 ml/min/1.73 ed GFR was 3.7 ml/min/1.73 5 years of treatment with 40– 5 years of treatment with 40– artan.
artan.3232 In RENAALIn RENAAL, th estimated GFR was estimated GFR was 3.4 years of t 3.4 years of t In then th d
telmisartan or 160 mg valsartan once daily, with add-on therapy as required to achieve blood pressure control (<130/80 mmHg). The primary analysis was a noninferiority test of the 24 h urinary protein excretion rate. Since valsartan is an established, renoprotective therapy,27 these
data confirm that telmisartan is an attractive option in these patients.
A sister trial to VIVALDI, A trial to compare telMisartan 40 mg titrated to 80 mg versus losArtan 100 mg in hypertensive type-2 DiabEtic patients with Overt nephropathy (AMADEO), is currently ongoing and will provide further valu-able information on the relative renoprotective effects of ARBs.39 A prespecified meta-analysis based on the pooled data of the AMADEO and VIVALDI trials will also be performed.
Maximizing blockade to increase efficacy
Increasing evidence shows that the doses of ARBs and ACE inhibitors that provide maximum blood-pressure-lowering effects might not provide maximum renoprotective effects. High-dose ARB therapy (not high-High-dose ACE inhibitor therapy, as this is unlikely to be well tolerated) or combined ARBs and ACE inhibitor therapy have been investigated in several trials. In an open-label, randomized study of 78 hyperten-sive patients with chronic, nondiabetic, biopsy-proven nephropathies, reductions in proteinuria were compared for patients receiving 80 mg telmisartan once daily and patients taking 80 mg twice daily over 25 months.40 Significant decreases were reported in proteinuria in both treatment groups (P <0.01), but urinary protein concentrations were reduced significantly more among patients receiving double-dose telmis-artan (P <0.01). Reduction of proteinuria to lower than 0.3 g/day was achieved in 40% of patients treated with the double dose compared with 15% taking the once-daily regimen. In addition, in patients taking 80 mg twice daily, serum creatinine values remained stable.
ACE inhibitors and ARBs act on different stages of the RAS cascade. An attractive alter-native to high-dose ARB therapy, therefore, is combination therapy.41 A meta-analysis included 21 studies of combination ACE inhibitor and ARB therapy in 654 patients with proteinuric renal disease.42 The addition of an ARB to ACE inhibitor therapy resulted in reductions of proteinuria in patients with or without diabetes (210 mg/day and 582 mg/ day, respectively). In one trial, 192 patients
received lisinopril or telmisartan for 6 months, after which half received add-on telmisartan or lisinopril. All patients who received combi-nation therapy derived additional benefit, amounting to around 30% further reductions in albuminuria.43
CONCLUSIONS
Angiotensin II represents an important thera-peutic target for effective reduction of blood pressure and for protection from progressive renal damage in susceptible patients. Specific blockade of the AT1 receptor by ARBs inhibits the pathophysiological effects of angiotensin II. The renoprotective effects of ARBs are convincing, with data consistently showing effective reduc-tions in proteinuria that are independent of effects on hypertension in patients with type 2 diabetic nephropathy. Furthermore, reductions in proteinuria correlate with reduced cardiovas-cular risk.
In comparative studies of telmisartan and other blood-pressure-lowering therapies or placebo, renoprotection, reduced proteinuria and decline in GFR to levels similar to expected age-related decline have been reported. Further reductions in proteinuria can be achieved by increasing the dose or by combining treatment with an ACE inhibitor. ARBs can, therefore, play an important part in reducing the progression of renal disease and can be expected to play an increasing role in treatment of patients with either established nephropathy or with known risk factors, such as diabetes or hypertension.
KEY POINTS [AUTHOR: PLEASE CHECK THE EXPANDED KEY POINTS.]
■ Injury to the vascular endothelium and glomerulus can be promoted by an activated renin–angiotensin system and, therefore, inhibition of this system provides renoprotection
■ RAS inhibition reduces proteinuria, which is a key factor in the progression of renal disease
■ Blood pressure control is essential to prevent progression to end-stage renal disease, but because the mechanisms of angiotensin receptor blockers and angiotensin-converting-enzyme inhibitors differ, the effectiveness of the latter might decline over time
■ Combination therapy with angiotensin receptor blockers and angiotensin-converting-enzyme inhibitors seems to produce additional blood-pressure-lowering effects to monotherapy
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ht not ht not effects. effects. High-h-dose ACE inhibitor dose ACE inhibitor likely to be well tolerated) ikely to be well tolerated) ARBs and ACE inhibitor therapy s and ACE inhibitor therapy en investigated in several trials. Inn investigated in several trials. I pen-label, randomized study of 78en-label, randomized study of 78 sive patients with chronic, non sive patients with chronic, proven nephropathies, r proven nephropathie were compared were compared telmisartan telmisar 80 m re convie con wing effective re wing effective r a that are independentthat are independen ertension in patients with type ertension in patients with ty c nephropathy. Furthermore, reducnephropathy. Furthermore, redu n proteinuria correlate with reduced n proteinuria correlate with reduce cular risk. cular risk. In comparative stud In comparative s other blood-pre other bloo placebo, r placebo, r and anPROOF
ten-ic, biopsy-c, biopsy ons in proteinuria proteinuria tients receiving 80 mg ients receiving 80 mg e daily and patients taking daily and patients taking daily over 25 months.daily over 25 months.4040 Significan Significan e reported in proteinuria e reported in proteinuria ps ( ps (PP <0.01), but uPP<0.01), but were reduce were r ece
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e in Gin G related declinlated decl reductions in pro reductions in pr increasing the dose increasing the d with an ACE inhibitan ACE in an important an importan of rena of rena iReferences
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t
PROO
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ROOF
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Acknowledgments
PAREXEL MMS provided writing assistance, comprising preparation of a draft from slides and audio transcript, preparation of figures and obtaining copyright permissions, proofreading, and reference checking.
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