Renal protection by inhibition of the renin-angiotensinaldosterone

Renal protection by inhibition of the renin-angiotensinaldosterone system Tomas Berl Key words: angiotensinconverting enzyme inhibitor, angiotensin receptor blocker, combination therapy, direct renin inhibitor, monotherapy, proteinuria Division of Renal Diseases and Hypertension, University of Colorado at Denver Health Sciences Center, Denver, Colorado, USA. Correspondence to: Tomas Berl, MD Division of Renal Diseases and Hypertension, University of Colorado at Denver Health Sciences Center, 4200 East Ninth Avenue, Box C281, BRB 423, Denver, CO 80262, USA. Tel: +1 303 315 7204 Fax: +1 303 315 0189 Email: Tomas.Berl@ uchsc.edu Abstract Renin-angiotensin-aldosterone system (RAAS) inhibition exerts a renoprotective effect independent of blood pressure reduction. Many studies using an end-point of proteinuria compared the effects of angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) monotherapy with combination ACE-I/ARB therapy. Despite methodological limitations, most studies suggest that combination therapy provides a greater antiproteinuric effect than monotherapy, perhaps because of more prolonged and complete RAAS inhibition. COOPERATE and ONTARGET used more robust end-points to study renoprotective effects. In COOPERATE, combination therapy resulted in significantly longer times to doubling serum creatinine or developing end-stage renal disease than trandolapril or losartan monotherapy. However, a secondary ONTARGET finding was that combination therapy significantly increased the risk for renal dysfunction compared with ramipril or telmisartan alone. Eventually, the VA NEPHRON-D trial should provide definitive data relating to patients with diabetic nephropathy. Results of AVOID suggest the renoprotective benefits of combination therapy extend to the direct renin inhibitors (DRI). In AVOID, combination therapy with aliskiren, a DRI, and losartan resulted in 20% greater protein excretion decrement than losartan monotherapy. Future trials should examine higher RAAS inhibitor doses, facilitate differentiation of renoprotective and antihypertensive effects of RAAS blockade, and use end-points that robustly demonstrate renoprotective effects. Introduction In the past 20 years, inhibitors of the reninangiotensin-aldosterone system (RAAS) have become a cornerstone for the treatment of hypertension. Similarly, RAAS inhibitors have been used increasingly in patients with underlying renal disease as mounting evidence has pointed to the agents having an antiproteinuric effect that is independent of blood pressure lowering. 1 This effect is considered important in light of two key observations. Several large interventional studies have uniformly found that proteinuria is a major risk factor for the progression of renal disease. 2-5 Furthermore, the reduction of proteinuria in patients with underlying diabetic nephropathy has been associated with a decreased risk for a renal end-point (e.g. doubling of serum creatinine, reaching end-stage renal disease). 3,4 A similar observation was seen in patients with nondiabetic kidney disease with lower levels of baseline proteinuria, 5 thereby demonstrating the importance of lowering protein excretion in a variety of renal disorders and across a broad spectrum of protein excretions. In view of these observations, it is not surprising that clinical studies have evaluated the effects of higher doses of angiotensin-converting enzyme inhibitors (ACE-I) 6,7 and angiotensin receptor blockers (ARB) 6,8 at doses exceeding those approved by the Food and Drug Administration for lowering blood pressure. Additionally, because RAAS intervention can be targeted at various points (figure 1), it has been postulated that combining more than one of these intervention points could lead to greater inhibition of the RAAS and a more robust decrement in protein excretion. Thus, there are four potential combinations of existing therapeutic agents. Furthermore, given that antagonists of aldosterone a downstream effector of angiotensin II (Ang II) have been shown to decrease protein excretion in patients with renal diseases, 9 the option of also using aldosterone inhibitors doubles the potential combinations to eight. In this review, a brief summary of the data is presented supporting the use of combination therapy with ACE-Is and ARBs compared with monotherapy using either 10.1177/1470320309102747 1

Figure 1 RAAS and points at which pharmacologic intervention can inhibit it. ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; AT 1 = angiotensin II type 1; DRI = direct renin inhibitor. 2 class of agents. Also presented are some results of emerging studies with a recently approved direct renin inhibitor (DRI), aliskiren. Comparison of the effects of combination ACE-I plus ARB therapy with ACE-I or ARB monotherapy on proteinuria A large number of clinical studies have compared the effects of dual RAAS blockade and single blockade with an ACE-I or an ARB on protein excretion as a surrogate for renal protection. The reader is referred to tables 4 and 5 in the metaanalysis conducted on these studies by Kunz et al. 10 Details of some of these studies, which are representative of the group as a whole, are presented in table 1. 11-17 Mogensen et al. 11 were the first investigators to conduct a randomised, parallel-group, doubleblind study comparing lisinopril 20 mg, candesartan 16 mg, and combination lisinopril plus candesartan in 199 patients with type 2 diabetes. Combination therapy with lisinopril plus candesartan provided a significant decrease in protein excretion compared with ARB monotherapy (p=0.04); however, the difference was not significant when compared with ACE-I monotherapy. In a small follow-up study (n=20), Jacobsen et al. 12 compared the antiproteinuric effects of benazepril 20 mg, valsartan 80 mg, and combination therapy with benazepril plus valsartan in a randomised, double-blind, placebo-controlled, crossover trial in patients with type 1 diabetes. In contrast to the Mogensen et al. findings, 11 a significant decrease in protein excretion was reported in the patients treated with benazepril 20 mg plus valsartan 80 mg compared with patients treated with monotherapy of either agent (p<0.05). 12 In a study with similar design, Jacobsen et al. 13 evaluated the effect of enalapril 40 mg, irbesartan 300 mg, and combination therapy with enalapril plus irbesartan in 24 patients with type 1 diabetes. Repeatedly, the combination of the ACE-I and ARB provided a significantly greater antiproteinuric effect than therapy with the ACE-I alone (p<0.001). Although these often-cited studies support the clinical use of dual RAAS inhibition with an ACE-I and an ARB, two study limitations may impact this interpretation in clinical practice. The first limitation relates to the difference in achieved blood pressure measurements among the treatment groups. Specifically, in the study by Mogensen et al., 11 the authors clearly state that in the group of patients who received the combination treatment after 12 weeks, there was a measurable further reduction in systolic and diastolic blood pressure. Similarly, the two studies by Jacobsen et al. 12,13 report 7 mmhg to 9 mmhg lower systolic and diastolic ambulatory blood pressure in the group receiving ACE-I/ARB combination therapy. It is therefore difficult, if not impossible, to ascertain whether the changes observed in protein excretion

Table 1 Combination of ACE-I plus ARB versus ACE-I or ARB. Combination better than monotherapy Blood pressure No. of patients lower in Reference End-point Condition Drugs ACE-I ARB combination Mogensen et al. 11 UACR n=199 Lisinopril 20 mg or candesartan No Yes Yes Type 2 diabetes 16 mg vs. lisinopril 20 mg + candesartan 16 mg Jacobsen et al. 12 Urinary n=20 Benazepril 20 mg or valsartan Yes Yes Yes albumin Type 1 diabetes 80 mg vs. benazepril 20 mg + valsartan 80 mg Jacobsen et al. 13 Urinary n=24 Enalapril 40 mg vs. enalapril Yes Yes albumin Type 1 diabetes 40 mg + irbesartan 300 mg Luno et al. 14 UACR n=45 Lisinopril to 40 mg or candesartan Yes Yes No Proteinuric to 32 mg vs. lisinopril nephropathy 20 mg + candesartan 16 mg Campbell et al. 15 UACR n=24 Benazepril 20 mg or valsartan Yes Yes No Nondiabetic 160 mg vs. benazepril proteinuria 10 mg + valsartan 80 mg Nakao et al. 16 Doubling n=263 Trandolopril 3 mg or losartan Yes Yes No serum Nondiabetic 100 mg vs. trandolopril creatinine proteinuria 3 mg + losartan 100 mg ESRD The ONTARGET Doubling serum n=25,620 Telmisartan 80 mg or ramipril No No Yes Investigators 17 creatinine 10 mg vs. telmisartan ESRD Death 80 mg + ramipril 10 mg Key: ESRD = end-stage renal disease; UACR = urinary albumin/creatinine ratio. were a consequence of more complete RAAS inhibition or decreased blood pressure. The second study limitation was the dosing used, which may in fact be partially responsible for the observed changes in blood pressure. Therefore, all three of these studies and two other studies 18,19 administered the same doses of ACE-I and ARB as monotherapy and as combination therapy, which might have resulted in more complete inhibition of RAAS with combination therapy than was achieved with either drug administered as monotherapy. This factor is particularly important because some studies have reported that the use of megadoses of monotherapy with ACE-Is or ARBs are associated with positive changes in protein excretion comparable to those reported using combination therapy with an ACE-I plus an ARB. 6-8 Several recent studies have avoided these design limitations. In a study of 45 patients with primary proteinuric nephropathies (>2 g protein/d), Luno et al. 14 described a significant decrease (p=0.023) in protein excretion with combination therapy of lisinopril (up to 20 mg) plus candesartan (up to 16 mg) versus monotherapy with either drug given at up to twice the original dose (lisinopril [up to 40 mg]; candesartan [up to 32 mg]; table 1). This dosing approach is more appropriate than the study design used in the earlier reports because it may provide equivalent RAAS inhibition in all treatment groups. 11-13,18,19 The study by Luno et al., 14 though limited in the number of patients enrolled, had merit in that it achieved equivalent blood pressure levels in all three treatment groups. Combination therapy with an ACE-I and an ARB resulted in a greater decrease in proteinuria than did monotherapy. A similar observation was reported by Campbell et al. 15 in a prospective, randomised, crossover study of 24 nondiabetic patients with proteinuria. Similar to the study design used by Luno et al., 14 Campbell et al. 15 administered twice the dose of an ACE-I (benazepril 20 mg) or an ARB (valsartan 160 mg) as monotherapy compared with the doses used for combination therapy (benazepril 10 mg plus valsartan 80 mg). This study design resulted in identical decreases in blood pressure reported as mean arterial pressure: 95 mmhg (benazepril 20 mg), 95 mmhg (valsartan 160 mg), and 94 mmhg 3

4 Figure 2 Percentage change from baseline for 24-hour urinary protein excretion rate, mean arterial pressure, and creatinine clearance. p<0.025 with Bonferroni adjustment. Data are mean±sem; n=24. Dosages: valsartan 160 mg; benazepril 20 mg; benazepril + valsartan 10 mg + 80 mg. 15 Reprinted with permission from Campbell R, Sangalli F, Perticucci E et al. Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Kidney Int 2003;63:1094-103. (benazepril 10 mg plus valsartan 80 mg). Although monotherapy with benazepril or valsartan lowered the albumin/creatinine ratio by 45.9% or 41.5%, respectively, combination therapy lowered the albumin/creatinine ratio by 56.0%, which was statistically greater than was achieved with either monotherapy (figure 2). 15 These blood pressure-lowering independent effects of combination therapy at comparable doses were subsequently reported by others. 20 It must be noted that not all clinical studies uniformly report a positive response from combination treatment with an ACE-I plus an ARB, even when proper dose adjustments have been made. For example, Esnault et al. 21 found no greater decrement in protein excretion in 18 proteinuric patients given ramipril 5 mg plus valsartan 80 mg compared with ramipril 10 mg or valsartan 160 mg. However, this study suggests, as has been previously proposed by others, 22,23 that the concomitant sodium balance may be another important determinant of the response to inhibitors of RAAS. Thus, patients who received ACE-I/ARB combination therapy displayed marked reductions in protein excretion when they were also given the diuretic furosemide. However, in the study by Esnault et al., 21 furosemide was not given to the monotherapy groups and was associated with significant decrements in systolic blood pressure. Most studies of RAAS blockers comparing the antiproteinuric effect of monotherapy with combination therapy lack sufficient power to establish a difference between the regimens. Therefore, a meta-analysis of existing studies was undertaken by Doulton et al. 24 The meta-analysis included analysis of eight independent clinical studies; it found that combination ACE-I/ARB therapy decreased protein excretion by 30% compared with ACE-I monotherapy and by 39% with ARB monotherapy. A more recent and exhaustive meta-analysis compared the antiproteinuric effect in the early phase (1 4 months) and the later phase (5 12 months) of treatment. 10 In the early phase of treatment, 14 studies were analysed to compare the antiproteinuric effects of combination therapy with an ACE-I plus ARB with those of ARB monotherapy. The ratio of means (95% confidence interval [CI]) favoured combination treatment (0.76 [0.68 0.85]). A similar result was observed in 21 studies when the comparator was ACE-I monotherapy (0.78 [0.72 0.84]). In the later phase of treatment, a smaller group of studies was available for analysis. Nonetheless, combination therapy was found to be superior to ARB monotherapy in seven studies (0.75 [0.61 0.92]). In the same studies, the ratio of means was 0.82 (0.67 1.01) when the comparator was ACE-I monotherapy. Evaluated together, these data suggest that combining an ACE-I and an ARB may provide a superior antiproteinuric effect than monotherapy with either agent. However, the superiority may be limited to conventional doses of ACE-Is and ARBs because higher than conventional doses of these agents also decrease protein excretion. 6-8,25 For example, in one of these studies, Hollenberg et al. 8 found that 320 mg and 640 mg of valsartan provide further antiproteinuric effect when compared to conventional dose of 160 mg. Thus, in the appropriate clinical setting, this approach may yield results that are comparable to combination therapy. No studies have been published comparing the two approaches. The underlying, unifying mechanism for inhibition of the RAAS may be the degree of inhibition of the system and of the generation of Ang II. This is strongly suggested by the observations of a study by Forclaz et al., 26 who investigated the antihypertensive response of monotherapy and combination therapy of two ARBs (losartan and telmisartan) on angiotensin I (Ang I) infusion (figure 3) in normotensive persons. 26 As expected, blockade of Ang II generation was not observed with standard doses of either ARB, but inhibition of blood pressure response to Ang I was seen when the dose of losartan (a short-acting ARB) was increased to 100 mg twice a day or when a standard dose of telmisartan (a long-acting ARB) was combined with the ACE-I. As Linas 27 suggests, these results support the view that the critical determinant of blood pressure response is longer (a full 24 hours) and more complete inhibition of the RAAS rather than physiologic interaction between an ACE-I and an ARB, as supported by the data depicted in figure 3.

Figure 3 Summary of blockade of blood pressure (BP) response to exogenous angiotensin I at trough in study groups (n=5 10 according to study protocols). Data are mean±sd; *p<0.01; bid = twice a day; qd = every day. 26 Reprinted with permission from Forclaz A, Maillard M, Nussberger J, Brunner HR, Burnier M. Angiotensin II receptor blockade: is there truly a benefit of adding an ACE inhibitor? Hypertension 2003;41:31-6. Renoprotection with combination ACE-I plus ARB therapy All the aforementioned studies used change in protein excretion as a surrogate for renal protection. A more robust end-point of renal protection is the ability of an intervention to alter the time to renal failure in patients with progressive renal disease. No review of this subject would be complete without a brief discussion of the COOPERATE trial, which compared ACE-I/ARB combination therapy with monotherapy and used a combined endpoint of time to doubling serum creatinine or development of end-stage renal disease (table 1). 16 In this study, 263 patients with moderately advanced renal insufficiency (glomerular flow rate, approximately 35 ml/min) were followed up for a median of 2.9 years (range, 3 months 3.3 years). The COOPERATE trial was terminated early because of the beneficial effect observed with combination therapy. Specifically, the hazard ratio of combination therapy compared with losartan monotherapy was 0.40 (95% CI, 0.17 0.69; p=0.016); compared with trandolapril monotherapy it was 0.38 (95% CI, 0.18 0.63; p=0.018). This effect occurred across the spectrum of baseline protein excretion and was independent of lowered blood pressure because it was similarly decreased in all three treatment groups. However, analysis of the ambulatory blood pressures in this study has raised questions about whether the effect was truly blood pressure independent. 28 Furthermore, serious concerns have been raised about the accuracy of the data and their analysis, 29 that if verified should lead to a negation of the trial. The effects of combination therapy on renal function were markedly different in the ONTARGET trial, whose final results have recently been published. 17 ONTARGET included 25,620 patients 85% with cardiovascular disease, 69% with hypertension, and 38% with diabetes who were randomly assigned to receive ramipril 10 mg, telmisartan 80 mg, or combination therapy. This was not a trial of patients with underlying renal disease because renal function at baseline was normal and only 13% of the patients had microalbuminuria. During the study, mean blood pressure was slightly lower in groups treated with telmisartan (a 0.9/0.6 mmhg greater reduction) and combination therapy (a 2.4/1.4 mmhg greater reduction) than in the group treated with ramipril (table 1). However, these did not result in a significant benefit in terms of the primary composite outcome (death from cardiovascular cause, myocardial infarction, or stroke or hospitalisation for heart failure). At a median follow-up of 56 months, the primary outcome had occurred in 16.5% of the ramipril group and 16.7% of the telmisartan group, indicating that telmisartan was noninferior to, but not superior to, ramipril (relative risk, 1.01; 95% CI, 0.94 1.09). Similarly, the primary outcome occurred in 16.3% of the combination therapy group (relative risk vs. ramipril, 0.99; 95% CI, 0.92 1.07). 17 Nephropathy was a secondary outcome of ONTARGET and the renal outcomes have been recently published. 30 The primary renal outcome was the composite of dialysis, doubling of serum 5

Figure 4 Kaplan-Meier curves for primary renal outcome (dialysis, doubling of serum creatinine, and death). 30 Reprinted with permission from Mann JF, Schmieder RE, McQueen M et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-53. 6 creatinine and death. While the telmisartan and ramipril arms did not differ from each other, the number of events was increased in the combination HR 1.09 [1.10 1.18], p=0.037 (figure 4). The secondary outcomes of dialysis and doubling of serum creatinine were also higher in the combination group. It must be pointed out that the great majority of the patients in this trial had normal renal function and were free of proteinuria. In fact, a subgroup analysis suggests that the worse outcome with the combination therapy occurred in patients who were not diabetic, not hypertensive, had neither micro nor macroalbuminuria, and had no over diabetic nephropathy. A study primarily aimed at patients at risk for progressive renal disease is still needed. The VA NEPHRON-D study (NCT00555217) may eventually provide more definitive data on the effect of the combination of an ACE-I and an ARB on the progression of kidney disease. 31 This Department of Veterans Affairs-sponsored trial, which is open for recruitment, will enrol patients with type 2 diabetes, an estimated glomerular filtration rate (GFR) of 30 to <90 ml/min/1.73 m 2, and albuminuria >300 mg/g creatinine. Patients will receive open-label losartan 100 mg in combination with blinded lisinopril 40 mg or placebo for up to 5 years. The primary study end-point will be a composite of reduction in estimated GFR of >50% in patients with baseline estimated GFR <60 ml/min/1.73 m 2, reduction in estimated GFR of 30 ml/min/1.73 m 2 in patients with baseline estimated GFR? 60 ml/min/1.73 m 2, progression to end-stage renal disease, or death. Emergence of DRIs With the recent development of DRIs, there is now the possibility of inhibiting RAAS at its point of activation (figure 1), 32 while simultaneously abrogating the stimulation of plasma renin activity (PRA) that accompanies the use of ACE-Is and ARBs. This approach appears to be a particularly attractive method for treating hypertension. Additionally, two recent studies have established that a DRI (aliskiren) can be combined with an ACE-I 33 or an ARB. 34 In both studies, the combination of these agents produced a more profound decrement in blood pressure compared with monotherapy. Specifically, the combination of aliskiren 300 mg plus ramipril 10 mg resulted in a greater lowering of mean sitting diastolic blood pressure than did monotherapy with either drug (p=0.004), 33 whereas administration of aliskiren 300 mg with valsartan 320 mg produced significant decrement in all blood pressure parameters versus monotherapy with either drug (p<0.001). 34 Additionally, aliskiren monotherapy reduced PRA by 66% 33 and 73%. 34 In combination with ramipril or valsartan, PRA was reduced by 48% 33 and 44%, 34 respectively (p<0.0001 for all values).

An exploratory study investigated the time course of the antiproteinuric and antihypertensive effects of direct renin inhibition by aliskiren in 15 evaluable patients with type 2 diabetes and microalbuminuria or macroalbuminuria. 35 After a 4-week washout of previous antihypertensive medications, patients received aliskiren 300 mg and furosemide daily for 28 days, followed by a 4-week withdrawal period. After initiation of treatment with aliskiren, there was a progressive reduction from baseline in urinary albumin/creatinine ratio (UACR): 17% after 2 to 4 days of treatment (p=0.04), 31% after 8 to 10 days (p<0.001), and 44% after 26 28 days (p<0.001). Mean 24-hour systolic blood pressure was significantly lower than baseline after 7, 14, and 28 days of treatment. Mean 24-hour diastolic blood pressure was not significantly different from baseline during the treatment period, but the baseline diastolic blood pressure was low (75 mmhg). Importantly, there was no significant correlation between the relative change from baseline in UACR and in 24-hour blood pressure (r=0.298, p=0.347). In addition, the time course of changes in UACR and 24-hour blood pressure was not concordant. Significant changes in UACR occurred earlier (days 2 4) than changes in 24-hour systolic blood pressure (day 7), and, over the duration of treatment with aliskiren, there was a progressive reduction from baseline in UACR but not blood pressure. Findings of this exploratory study suggest that the antiproteinuric effect of aliskiren is, at least in part, blood pressure independent. The AVOID trial was a randomised, double-blind, placebo-controlled study that enrolled 599 hypertensive patients with type 2 diabetes and nephropathy. 36 After a 12- to 14-week, open-label phase of treatment with losartan 100 mg, patients were randomly assigned to receive aliskiren (increasing from 150 to 300 mg) or placebo. The primary end-point was UACR at 24 weeks. Despite marginal differences in reductions in blood pressure (systolic, 2 mmhg lower [p=0.07], and diastolic, 1 mm Hg lower [p=0.08], in patients who received aliskiren), the aliskiren group had a 20% greater reduction in UACR compared with the losartan plus placebo group (95% CI, 9 30; p<0.001). Whether a comparable antiproteinuric effect could have been obtained by increasing the dose of losartan to 200 mg was not explored. Aliskiren was well tolerated, but there was a higher incidence of hyperkalemia (6.0 meq/l) with aliskiren than with placebo (4.7% vs. 1.7%, respectively; p=0.06). Hyperkalaemia was transient, and none of the aliskiren-treated patients dis con tinued the study drug. This study showed that the addition of aliskiren provided an incremental antiproteinuric effect that appeared to be independent of blood pressure lowering in hyper tensive diabetic patients who had residual proteinuria despite treatment with an ARB. Further studies on the effect of DRIs on the progression of renal disease are eagerly awaited. Conclusion Increasing evidence indicates the inhibition of RAAS may exert a renoprotective effect that is independent of its effect on blood pressure reduction. Many studies that have used an end-point of proteinuria as a surrogate for renal protection have compared the effects of a single blockade of RAAS using an ACE-I or an ARB with a combined blockade using both an ACE-I and an ARB. Although some of these studies had methodological limitations, the results of most individual studies and two meta-analyses suggest that combining an ACE-I and an ARB may provide an antiproteinuric effect superior to that of monotherapy with either type of agent. It remains uncertain whether this effect is limited to conventional doses of ACE-Is or ARBs, or whether it also pertains to doses that exceed those approved for the treatment of hypertension. Available data suggest that the beneficial effect achieved with combination therapy derives from the more prolonged and complete inhibition of RAAS rather than from a physiologic interaction between an ACE-I and an ARB. The renoprotective effects of monotherapy with an ACE-I or an ARB compared with combination therapy have been examined more directly in the COOPERATE and ONTARGET trials. In COOPERATE, combination therapy with trandolapril and losartan slowed the progression of nondiabetic renal disease compared with either agent alone, but the veracity of the data has been questioned. However, a secondary finding of ONTARGET was that combination therapy significantly increased the risk for adverse renal outcomes compared with monotherapy with ramipril. Eventually, more definitive data are expected from the VA NEPHRON-D trial, in which patients with diabetic nephropathy will receive losartan monotherapy or losartan/lisinopril combination therapy. Data from the AVOID trial suggest that the addition of aliskiren to an ARB provides an antiproteinuric effect additional to that of the ARB alone. In AVOID, combination therapy with aliskiren and losartan resulted in a 20% greater decrease in UACR than losartan monotherapy, an effect independent of blood pressure reduction. Given the methodological limitations of existing studies, additional investigation is warranted. These trials should examine the efficacy and safety of 7

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