renin inhibitors: optimal strategy for renal protection

Renin Inhibitors: Optimal Strategy for Renal Protection

Roland E. Schmieder, MD

Corresponding authorRoland E. Schmieder, MDDepartment of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Krankenhausstraße 12, 91054 Erlangen, Germany.E-mail: [email protected]

Current Hypertension Reports 2007, 9:415–421Current Medicine Group LLC ISSN 1522-6417Copyright © 2007 by Current Medicine Group LLC

Diabetic nephropathy and hypertension are the major causes of chronic kidney disease. The renin system plays a key role in the control of blood pressure (BP), as well as in the regulation of renal and adrenal func-tion. Chronic activation of the renin system can lead to organ damage, particularly renal damage; increas-ing evidence indicates that suppression of the renin system can provide renal protection. Despite the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), the renin system is not completely suppressed. The direct renin inhibitors (DRIs) provide suppression of the entire renin system at the rate-limiting step. Studies in humans with early DRIs indicated potential renoprotective effects, but these agents failed in clinical development due to poor oral bioavailability. Aliskiren is a new orally active DRI with proven BP-lowering effects. Animal studies indicate that aliskiren may provide renal protection, and data from human studies are anticipated.

IntroductionChronic kidney disease or chronic renal failure is charac-terized by a slow progressive loss of renal function during a period of months or years. If chronic renal failure pro-gresses unchecked it can lead to end-stage renal disease (ESRD), requiring long-term dialysis or possibly kidney transplantation. ESRD is disabling and is associated with a high morbidity and mortality rate. Unfortunately, the incidence of ESRD is increasing. Epidemiologic studies indicate that 20 million Americans have chronic kidney disease, with another 20 million at risk of developing it [1]. In the United States alone, over 104,000 patients began treatment for ESRD in 2004 [2].

The two main causes of chronic kidney disease are diabetic nephropathy and arterial hypertension, which are responsible for up to two thirds of cases [1]. Furthermore, hypertension is a well-documented risk factor for myo-cardial infarction (MI) and stroke [3]. As a consequence, antihypertensive agents have been shown to significantly reduce the incidence of stroke, MI, and heart failure [4]. Studies indicate that antihypertensive agents belonging to the angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) classes slow the deterioration of renal function in diabetic patients with kidney disease [5•]. However, despite the avail-ability of antihypertensive agents and evidence of their effectiveness, most patients with hypertension do not have blood pressure (BP) at or below the recommended target of 140/90 mm Hg (< 130/80 for patients with dia-betes or chronic kidney disease, and < 120/75 mm Hg for patients with proteinuria) [3]. This explains, in part, why the progression of chronic renal failure is not stopped. Additionally, incomplete blockade of the effects of pro-renin/renin, angiotensin, and aldosterone may be another reason for the continued progression.

The Renin SystemThe renin-angiotensin-aldosterone system is a hormonal system that plays a key role in the control of cardiovascular (CV), renal, and adrenal function by regulating fluid vol-ume, electrolyte balance, and arterial pressure [6]. Because the role of prorenin/renin and its receptor is increasingly apparent, particularly in diabetic nephropathy, we refer to the system as the renin system in this article.

The renin system is stimulated by a reduction in fluid volume, leading to release of renin from the kidney. Renin, a proteinase enzyme formed by juxtaglomerular cells in the kidney, catalyzes the conversion of angiotensinogen to angio-tensin I (Ang I), a peptide with no pharmacologic activity. In turn, Ang I is converted by angiotensin-converting enzyme (ACE) to angiotensin II (Ang II), the principal effector peptide of the renin system. Binding of Ang II to the Ang II subtype-1 receptor (AT1) elicits generalized vasoconstric-tion and increased release of noradrenalin from sympathetic nerve terminals, reinforcing vasoconstriction and increas-ing both the rate and force of heart contractions. In the

416 Antihypertensive Therapy: Renal Injury

kidneys, the effect of vasoconstriction mediated by Ang II reduces blood flow, increases intraglomerular pressure by vasoconstriction at the postglomerular site, and increases the reabsorption of salt and water. Ang II also stimulates the proximal tubular reabsorption of sodium ions and secretion of aldosterone from the adrenal cortex. In turn, aldosterone markedly increases sodium reabsorption by the kidney tubules, increasing sodium levels in the extracellular fluid, leading to water retention, increased extracellular fluid vol-ume, and, ultimately, to elevated arterial BP [7].

Under normal conditions, a negative feedback loop ensures that overactivation of the renin system does not occur. This feedback loop is activated when there is suf-ficient stimulation of AT1 receptors by Ang II and leads to reduced renin release. However, in pathologic conditions, the renin system can become chronically activated.

Tissue-specific renin systemIn addition to the renin system that circulates in the vascu-lature (the classical renin system), local tissue renin systems have been identified [6]. Chronic activation of either the classical or local tissue renin systems will ultimately lead to organ damage, as well as perpetuating elevated BP [8,9].

In tissue-specific renin systems, Ang II is secreted at the tissue level and exerts both autocrine and paracrine effects. Ang II can also be generated by non-ACE path-ways, such as chymases and endopeptidases [10]. Under physiologic conditions, tissue Ang II regulates vascular structure and tone, but in chronic hypertension there is increasing evidence that tissue Ang II is involved in the development of organ damage via oxidative, proliferative, inflammatory, and fibrotic mechanisms [11].

Local tissue Ang II directly influences endothelial func-tion. Normal endothelial function is dependent on the cell redox state, which is determined by the homeostatic bal-ance between nitric oxide (NO) and reactive oxygen species (ROS) [11]. Increased levels of Ang II in the endothelium cause the generation of ROS and reduction of NO activity, leading to oxidative stress. In turn, this leads to endothelial dysfunction and cell growth. Furthermore, there is inflam-mation triggered by the activation of nuclear factor- B(NF- B), monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule (VCAM), and release of the cytokines interleukin-6 (IL-6) and tumor necrosis factor- (TNF- ). VCAM and cytokines also increase the binding of inflammatory cells to the endothelial surface, leading to vascular inflammation and thrombosis [11].

Tissue-specific Ang II is involved in vascular remodel-ing by inducing the expression of autocrine growth factors in vascular smooth muscle cells [11]. In addition, Ang II is implicated in the development of atherosclerotic plaques by stimulating the release of endothelin-1, proliferation of smooth muscle cells, and formation of foam cells. Plaque stability and rupture is also influenced by Ang II via the production of matrix metalloproteinase enzymes. Tissue Ang II is also implicated in the development of a pro-

thrombotic state via its effect on the endothelium, which leads to an alteration in the balance between fibrinolytic and coagulation systems. Ang II, acting on angiotensin receptors of endothelial cells, induces the formation of plasminogen activator inhibitor type-1 (PAI-1), thereby promoting the development of a prothrombotic state [11].

Intrarenal renin systemStudies strongly suggest that Ang II is the mediator of progressive kidney damage in diabetic nephropathy [12–14,15••]. It is well known that Ang II raises BP through direct vasoconstrictor effects in systemic ves-sels, but its influence in the kidney also affects arterial pressure [8]. Increased levels of Ang II in the kidneys are associated with decreased renal blood flow and reduced glomerular filtration rate, together with increased sodium retention, proteinuria, and glomerulosclerosis [6,13]. Reduced blood flow to the kidneys is of particular importance because the kidney receives a higher blood flow per gram of organ weight than any other organ in the body—20% of the cardiac output at any time. When the renal blood flow decreases, this leads to retention of fluid and sodium with the consequence of increased peripheral vascular resistance. The normal physiologic response to a decrease in renal blood flow is release of renin, leading to increased levels of Ang II and, hence, the propagation of a vicious cycle.

The impact of the intrarenal renin system is further enhanced by the progressive increase in intrarenal Ang II. This high level of intrarenal Ang II cannot be fully explained by equilibration from Ang II in the circulation, and has been found to be particularly high in models of hypertension [13] and in patients with diabetes [14]. Fur-thermore, there is increasing evidence that many types of hypertension and related target organ damage are caused by inappropriate activation of the intrarenal renin system [13,15••]. The continuous activation of the intrarenal renin system results in excessive water and salt retention followed by volume-dependent blood pressure increase and long-term proliferation of glomerular endothelial cells, ultimately leading to renal injury [16].

The kidney is also the site for cleavage of prorenin to form renin. A variety of proteases are able to cleave renin from prorenin, some of which are located in the kidney. In normal circumstances, the plasma concentration of prorenin is greater than that of renin and prorenin does not exert any physiologic effect on renal homeostasis. However, a review of studies indicates that markedly elevated concentrations of plasma prorenin are associated with incipient nephropathy and proliferative retinopathy [17•]. Furthermore, data also suggest that in individuals with diabetes, especially those with microalbuminuria, increases in renin precede the development of early dia-betic nephropathy [17•]. Thus, the renin system, and possibly prorenin, plays a profound role in the develop-ment of chronic renal insufficiency.

Renin Inhibitors: Optimal Strategy for Renal Protection Schmieder 417

Drugs Acting on the Renin SystemThere are several antihypertensive classes of drug that elicit their effect through suppression of the renin system; these include the ACEIs, ARBs, and direct renin inhibi-tors (DRIs) (Fig. 1).

ACEIs inhibit the ACE enzyme and prevent the con-version of Ang I to Ang II, thereby reducing levels of Ang II. The reduction in Ang II leads to reduced vaso-constriction predominantly at the postglomerular site, reduced aldosterone leading to decreased sodium and water reabsorption in the kidney, and decreased fluid vol-ume. Complete suppression of the renin system by ACEIs is limited by non-ACE pathways, such as chymases and endopeptidases, which provide an alternative method for the conversion of Ang I to Ang II [10].

Unlike ACEIs, ARBs do not decrease circulating levels of Ang II, but block the action of Ang II at AT1 receptors. The currently available ARBs are all specific for AT1 receptors, and any activity of Ang II at the Ang II subtype-2 (AT2) receptors will be unaffected. Recent investigations have suggested a role for the AT2 receptor in CV, brain, and renal function as well as in processes involved in development, cell differentiation, tissue repair, and apoptosis [7]. However, whether the AT2 recep-tor has a positive or negative role in hypertension is still under debate [18].

Studies have shown that both ACEIs and ARBs have beneficial effects on renal disease [19–21]. Currently, the ARBs losartan and irbesartan are approved for the treat-ment of nephropathy in patients with type 2 diabetes and hypertension. In the Irbesartan in Diabetic Nephropathy Trial (IDNT), a randomized, double-blind clinical trial, 1715 patients with hypertension and nephropathy due to type 2 diabetes received treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo [21]. The pri-mary endpoint was a composite of a doubling of the baseline

serum creatinine concentration, the development of ESRD, or death from any cause. Irbesartan significantly reduced the risk of the combined primary endpoint by 23% compared with amlodipine (P = 0.006), and by 20% compared with placebo (P = 0.02). For the endpoint doubling of serum cre-atinine concentration, irbesartan significantly reduced the risk by 33% compared with placebo (P = 0.003) and 37% compared with amlodipine (P = 0.07).

Similarly, the relative risk of ESRD (defined as the initiation of dialysis, renal transplantation, or a serum creatinine concentration of 6.0 mg/dL or 530 mol/L) was 23% lower in the irbesartan group than in either the placebo or amlodipine group (P = NS for both vs irbesar-tan) [21]. Interestingly, in an assessment of the effect of study medications (irbesartan, amlodipine, and placebo) on progressive renal failure and all-cause mortality in dia-betic patients with optimal BP control, the renoprotective effect of irbesartan was observed in patients with optimal BP control (systolic BP < 134 mm Hg) [22••].

The renoprotective effects of losartan were demon-strated in the Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus (NIDDM) with the Angio-tensin II Antagonist Losartan (RENAAL) trial [20]. This was a randomized, double-blind study that compared the renal effects of losartan (50–100 mg once daily) and pla-cebo in patients with type 2 diabetes and nephropathy. Losartan significantly reduced the risk of the primary composite endpoint (doubling of the baseline serum cre-atinine concentration, ESRD, or death) by 16% compared with placebo (P = 0.02). In addition, losartan significantly reduced the incidence of a doubling of the serum cre-atinine concentration by 25% (P = 0.006) and ESRD by 28% (P = 0.002) compared with placebo [20].

Data from animal and human studies suggest that the renoprotective effects of ARBs arise both from blockade of the intrarenal renin system and via BP-lowering effects.

Feedback loop

Direct renin inhibitor

PRA ACEIs

Figure 1. Modulators of the renin system. ACE—angiotensin-converting enzyme; ACEI—angiotensin-converting enzyme inhibitor; Ang I—angiotensin I; Ang II—angiotensin II; ARB—angiotensin II receptor blocker; AT1—angiotensin II subtype-1 receptor. (Adapted from Weber and Giles [23].)


However, although ARBs reduced the progression of renal disease, it was not halted. Likewise, proteinuria was reduced, but still remained above the normal range. This suggests that there is room for improvement in renopro-tection above and beyond what is offered by ARBs and ACEIs. It is hypothesized that further renoprotective ben-efits may occur with a more fully effective blockade of the renin system [23]. In support of this hypothesis, studies have shown that significantly improved renoprotective effects can be achieved by either increasing the dose of ARB [24] or combining an ACEI and an ARB [25,26].

A study with ultra-high-dose candesartan in patients with normal or mildly impaired renal function and protein-uria showed that 12-weeks’ double-blind treatment with candesartan 64 mg/d provided a significantly greater reduc-tion in proteinuria compared with candesartan 32 mg/d with similar changes in BP (24-hour ambulatory BP), sodium excretion, and renal hemodynamics [27]. Similarly, in 52 patients with type 2 diabetes and microalbuminuria who received ultra-high doses of irbesartan (300, 600, and 900 mg once daily for 2 months), urinary albumin excretion rate was significantly reduced by all doses of irbesartan (P < 0.01), with the 900-mg dose providing a sig-nificantly greater reduction than the 600- and 300-mg doses (P = 0.02) [24]. All doses of irbesartan significantly reduced ambulatory BP and glomerular filtration rate.

Renoprotective effects of combining an ACEI and an ARB were demonstrated in the Combination Treatment of Angiotensin II Receptor Blocker and Angiotensin-Converting Enzyme Inhibitor in Non-diabetic Renal Disease (COOPERATE) study, which evaluated the renoprotective effects of a combination of trandolapril and losartan [25]. Significantly fewer patients achieved the combined primary endpoint (time to doubling of serum creatinine concen-tration or ESRD) with the combination treatment than with either of the respective monotherapies (11% vs. 23% with both monotherapies; P = 0.016) [25]. The Candesar-tan And Lisinopril Microalbuminuria (CALM) study of patients with microalbuminuria, hypertension, and type 2 diabetes assessed the renoprotection provided by the ARB candesartan combined with the ACEI lisinopril [26]. There was a significantly greater reduction from baseline in uri-nary albumin-creatinine ratio with combination treatment (50%, P < 0.001) than with candesartan (24%, P = 0.05) or lisinopril (39%, P < 0.001).

These data provide some evidence that increasing sup-pression of the renin system beyond that achievable with currently approved doses of ACEI or ARB monotherapy can lead to improved renoprotection. However, it is impor-tant to note that in these studies, renal damage and ESRD were delayed, but not stopped. Furthermore, some patients who received ACEI/ARB combination therapy or ultra-high doses of ARB still showed signs of renal damage (ie, they developed the primary endpoint of the study). It is possible that alternative methods of suppressing the renin system may be required in order to optimize renoprotection.

Direct renin inhibitorsActivation of renin is the first and also the rate-limiting step in the renin system cascade (Fig. 1). Therefore, inhi-bition of renin activity is the logical method to provide suppression of the entire system and was identified as a therapeutic target as long ago as 1957. Indeed, attempts to develop DRIs have been ongoing for more than 30 years, but until recently were limited by lack of oral bioavail-ability, lack of clinical efficacy, short plasma half-lives, and high costs of synthesis [28]. Aliskiren is the first orally effective DRI [29], and is now approved by the US Food and Drug Administration (FDA) for the treatment of hypertension.

DRIs reduce the formation of both Ang I and Ang II, whether generated by ACE-dependent or independent pathways, thereby reducing the stimulation of AT1 recep-tors at various sites. This is due to inhibition of the rate of generation of Ang I, which provides an indication of the activity of the renin system (ie, reduced plasma renin activity [PRA]). However, with DRIs, the activity of the released renin is inhibited. This results in suppression of the renin system, as indicated by reduced levels of PRA with DRIs [30,31]. Moreover, the compensatory rise in PRA observed with an ACEI or ARB is neutralized by the addition of a DRI, indicating effective suppression of the renin system [31,32•].

Because renin is highly specific for its substrate, angio-tensinogen, DRIs binding at the active site of renin with subsequent inhibition of Ang I synthesis may offer addi-tional advantages over ACEIs. For example, with ACEIs, high levels of Ang I are able to be converted to Ang II via non-ACE pathways. Furthermore, ACE is not specific for Ang I and can interact with other substrates such as brady-kinin and prostaglandins to evoke unwanted side effects.

In addition to the enzymatic action of renin, its inter-action with a recently identified renin receptor may be implicated in organ damage. This receptor, named the (pro)renin receptor, is capable of binding both renin and its inactive precursor prorenin [6]. The (pro)renin receptor is expressed in highest levels in the heart and brain, and in lower levels in the kidney and liver. In the kidney, the (pro)renin receptor is localized in glomerular mesangium and in the subendothelium of kidney artery, associated to smooth muscle cells and colocalized with renin [33]. Binding of renin to the (pro)renin receptor induces a series of intracellular events including the activation of the mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK) 1, and ERK 2, which is not attributable to the generation of Ang II [34••]. Binding of renin also leads to a fourfold increase in the catalytic conversion of angiotensinogen to Ang I [33] at the cell surface (a local or tissue renin system). It is speculated that this enhanced catalytic activity may provoke further organ damage and, consequently, as DRIs may modulate the receptor-mediated effects of renin, it is hypothesized that DRI might provide additional protection over that


of other renin system modulators [34••]. This has to be proven in future trials.

Antihypertensive effects of direct renin inhibitorsThe antihypertensive efficacy of several DRIs has been proven. Volunteer studies demonstrated antihyperten-sive effects of the renin inhibitors H-142, R-pep-27, and zankiren [35–37]. Studies in patients with hypertension indicated that remikiren provided similar antihypertensive efficacy to captopril, and enalkiren significantly reduced BP from baseline [38,39]. Despite the antihypertensive effects of early DRIs, these agents did not make it into clinical development due to poor oral bioavailability.

Aliskiren is the first DRI to gain FDA approval for the treatment of hypertension. Large phase III studies have shown that aliskiren provides significant dose-depen-dent reductions in BP from baseline as a monotherapy [40,41••]; reductions are similar to those with irbesartan [41••]. This effect occurs irrespective of age or race [42•]. Studies in patients with severe hypertension indicate that aliskiren provides similar antihypertensive effects to ACEIs [43]. When aliskiren is used in combination with ACEIs, calcium-channel blockers, or diuretics, additional antihypertensive effects are demonstrated [30,44–46]. Aliskiren has demonstrated 24-hour BP control [47], a lack of rebound effect after treatment discontinuation [48,49], and long-term (12-month) antihypertensive efficacy [49].

Renoprotective effects of direct renin inhibitorsSeveral studies have indicated that DRIs have renal effects that may translate into long-term renal protection. For example, studies in patients with hypertension and in normotensive individuals have shown that DRIs have a remarkable renal vasodilatory effect, leading to increased renal plasma flow [50,51]. Studies in patients with hyper-tension and normal or impaired renal function showed that orally administered remikiren led to significantly increased renal plasma flow and significant sodium loss, together with a stable glomerular filtration rate [51]. Furthermore, proteinuria significantly decreased, with the greatest reductions observed in patients with overt proteinuria at baseline. In addition to these renal effects, remikiren also significantly reduced mean arterial pres-sure from baseline, with the effect being more pronounced in patients with renal function impairment [51].

Renoprotection has been observed in animal studies with the DRI aliskiren. The use of animal models to test aliski-ren was particularly challenging because aliskiren is highly specific for human renin. One animal model that was devel-oped and used was the double transgenic rat (dTGR), which expresses human renin and angiotensinogen, and exhibits elevated albuminuria and renal macrophage infiltration—markers of kidney damage. Using this model, aliskiren 0.3 and 3 mg/kg/d administered subcutaneously was as effective as valsartan (10 mg/kg/d given orally) in preventing albu-minuria and renal macrophage infiltration [52••]. Because

valsartan 10 mg/kg/d had previously demonstrated complete renal protection in the dTGR model, this suggests that aliski-ren also attenuates renal damage. The dTGR model showed that aliskiren significantly reduces albuminuria, renal fibro-sis, and cell infiltration into the kidney to a similar extent as losartan [53]. In a further study, dTGR received aliskiren 3 mg/kg for 2 weeks. Treatment was stopped, but monitor-ing continued for a further 2 weeks. Treatment with aliskiren rapidly reversed existing albuminuria and this response persisted after stopping treatment, despite BP returning to baseline levels [54].

Using an animal model of hypertension and diabetes, in which animals develop severe renal damage, aliskiren prevented the development of albuminuria over a 68-day period [55]. In addition, aliskiren significantly reduced the expression of transforming growth factor- (TGF- ), a protein implicated in renal fibrosis during the progres-sion of diabetic nephropathy.

Taken together, these animal studies suggest that aliski-ren will elicit renal protection in patients with hypertension. The results of extensive ongoing studies evaluating the effects of aliskiren on surrogate markers of organ damage are eagerly awaited. In particular, the ongoing Aliskiren in the eValuation of prOteinuria In Diabetes (AVOID) study is designed to evaluate the effect of aliskiren on urinary albu-min-creatinine ratio in patients with hypertension, type 2 diabetes, and proteinuria.

ConclusionsDiabetic nephropathy and hypertension are the major causes of chronic kidney disease. Furthermore, hyper-tension is a well-documented risk factor for CV disease; consequently, the goal of antihypertensive treatment is to provide long-term lowering of BP, thereby preventing CV and renal damage, and reducing mortality.

The renin system is the major system implicated in the control of BP, as well as in the regulation of renal and adrenal function. Activation of the circulating renin system and local tissue renin systems can lead to organ damage, particularly renal damage. Evidence suggests that suppression of the renin system offers benefits beyond BP lowering, and therefore it is logical to assume that more effective suppression of the whole system may offer additional benefits to those offered by ARBs and ACEIs. In terms of renal protection, data from studies of ACEIs and ARBs indicate that inhibition of the renin system can provide renal protection beyond blood pressure control. However, neither of these drug classes provides complete suppression of the renin system. It is hypothesized that DRIs, which suppress the renin system at the rate-limiting step of Ang II synthesis, may provide further improved renal protection.

Studies in humans with early DRIs indicate a poten-tial renoprotective effect, but development of these agents was discontinued for several reasons, including low oral


bioavailability, lack of clinical efficacy, short plasma half-lives, and high costs of synthesis. Aliskiren is a new orally active DRI with proven BP-lowering effects. Animal studies indicate that aliskiren may provide renal protec-tion, and results from the AVOID study are awaited to determine if the hypothesized renoprotection is achieved in humans.

AcknowledgmentThe author would like to thank medical writer Neil Mar-mont for assistance in drafting this manuscript.

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This review describes the features of aliskiren, the first DRI to achieve widespread clinical exposure, and the biochemical differentiation that exists between the various classes of renin system inhibitors.35. Webb DJ, Manhem PJ, Ball SG, et al.: Clinical and

biochemical effects of the renin inhibitor H142 in humans. J Cardiovasc Pharmacol 1987, 10:S69–74.

36. Zusman RM, Hui KY, Nussberger J, et al.: R-PEP-27, a potent renin inhibitor, decreases plasma angiotensin II and blood pressure in normal volunteers. Am J Hypertens 1994, 7:295–301.

37. Menard J, Boger RS, Moyse DM, et al.: Dose-dependent effects of the renin inhibitor zankiren HCl after a single oral dose in mildly sodium-depleted normotensive subjects. Circulation 1995, 91:330–338.

38. Azizi M, Guyene TT, Chatellier G, Menard J: Blood pressure effects of acute intravenous renin or oral angiotensin convert-ing enzyme inhibition in essential hypertension. J Hypertens 1994, 12:419–427.

39. Neutel JM, Luther RR, Boger RS, Weber MA: Immediate blood pressure effects of the renin inhibitor enalkiren and the angiotensin-converting enzyme inhibitor enalaprilat. Am Heart J 1991, 122:1094–1100.

40. Oh B-H, Chung J, Khan M, et al.: Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and placebo-like tolerability in patients with hypertension. J Am Coll Cardiol 2006, 47:370A.

41.•• Gradman AH, Schmieder RE, Lins RL, et al.: Aliskiren, a novel orally effective renin inhibitor, provides dose-depen-dent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005, 111:1012–1018.

When given as once-daily monotherapy to patients with mild-to-moderate hypertension, aliskiren has been shown to provide dose-dependent reductions in blood pressure and placebolike tolerability.42.• Weir MR, Bush C, Zhang J, et al.: Antihypertensive efficacy

and safety of the oral renin inhibitor aliskiren in patients with hypertension: a pooled analysis. Eur Heart J 2006, 27:299.

This abstract summarized a pooled analysis across clinical stud-ies involving several thousand patients with mild-to-moderate hypertension. Aliskiren had comparable antihypertensive efficacy regardless of patient age.

43. Strasser RH, Puig JG, Farsang C, et al.: The oral renin inhibitor aliskiren has comparable safety and efficacy to lisinopril in patients with severe hypertension. J Hypertens 2006, 24:99–100.

44. Uresin Y, Taylor A, Kilo C, et al.: Aliskiren, a novel renin inhibitor, has greater BP lowering than ramipril and addi-tional BP lowering when combined with ramipril in patients with diabetes and hypertension. J Hypertens 2006, 24:S82.

45. Villamil A, Chrysant S, Calhoun D, et al.: The novel oral renin inhibitor aliskiren provides effective blood pressure control in patients with hypertension when used alone or in combination with hydrochlorothiazide. J Clin Hypertens 2006, 8:A100.

46. Munger MA, Drummond W, Essop MR, et al.: Aliskiren as add-on to amlodipine provides significant additional blood pressure lowering without increased oedema associated with doubling the amlodipine dose. Eur Heart J 2006, 27:117.

47. Mitchell J, Oh B, Herron J, et al.: Once-daily aliskiren provides effective, smooth 24-hour blood pressure control in patients with hypertension. J Clin Hypertens 2006, 8:A93.

48. Herron J, Mitchell J, Oh B, et al.: The novel renin inhibitor aliskiren is not associated with rebound effects on blood pressure or plasma renin activity following treatment withdrawal. J Clin Hypertens 2006, 8:A86–87.

49. Sica D, Gradman A, Lederballe O, et al.: Aliskiren, a novel renin inhibitor, is well tolerated and has sustained BP-low-ering effects alone or in combination with HCTZ during long-term (52 weeks) treatment of hypertension. Eur Heart J 2006, 27:121.

50. Fisher ND, Hollenberg N: Renal vascular responses to renin inhibition with zankiren in men. Clin Pharmacol Ther 1995, 57:342–348.

51. van Paassen P, de Zeeuw D, Navis G, de Jong PE: Renal and systemic effects of continued treatment with renin inhibi-tor remikiren in hypertensive patients with normal and impaired renal function. Nephrol Dial Transplant 2000, 15:637–643.

52.•• Pilz B, Shagdarsuren E, Wellner M, et al.: Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertension 2005, 46:569–576.

Double transgenic rats expressing the human renin and angiotensin genes develop hypertension with severe organ damage. This study describes the reversal of cardiac hypertrophy, albuminuria, and renal macrophage inflammation after administration of either aliskiren or valsartan to these rats.53. Fiebeler A, Shagdarsuren E, Pilz B, et al.: Low-dose renin

inhibitor and AT1 receptor blocker ameliorate angiotensin II-induced end-organ damage despite persistence of hyper-tension. Results presented at Renal Week. Philadelphia, PA; November 8–13, 2005.

54. Feldman DL, Jin L, Miserindino-Moltini R, et al.: Aliskiren, a human renin inhibitor induces persistent renoprotection comparable to ACE inhibition in double transgenic rats (dTGR). Am J Hypertens 2005, 8:230A.

55. Feldman DL, Jin L, Miserindino-Moltini R, et al.: The renin inhibitor aliskiren ameliorates hypertensive diabetic nephropa-thy in transgenic (nRen-2)27 (Ren-2) rats. Results presented at Renal Week. Philadelphia, PA; November 8–13, 2005.

renin inhibitors: optimal strategy for renal protection

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