Maximum renal responses to renin inhibition in healthy study participants: VTP-27999 versus aliskiren.

BACKGROUND: Renin inhibition with aliskiren induced the largest increases in renal plasma flow (RPF) in salt-depleted healthy volunteers of all renin-angiotensin system (RAS) blockers. However, given its side-effects at doses higher than 300 mg, no maximum effect of renin inhibition could be established. We hypothesized that VTP-27999, a novel renin inhibitor without major side-effects at high doses, would allow us to establish this. METHODS AND RESULTS: The effects of escalating VTP-27999 doses (75-600 mg) on RPF, glomerular filtration rate (GFR), and plasma RAS components were compared with those of 300 mg aliskiren in 22 normal volunteers on a low-sodium diet. VTP-27999 dose-dependently increased RPF and GFR; its effects on both parameters at 600 mg (increases of 18 ±â€Š4 and 20 ±â€Š4%, respectively) were equivalent to those at 300 mg, indicating that a maximum had been reached. The effects of 300 mg aliskiren (increases of 13 ±â€Š5 and 8 ±â€Š6%, respectively; P < 0.01 vs. 300 and 600 mg VTP-27999) resembled those of 150 mg VTP-27999. VTP-27999 dose-dependently increased renin, and lowered plasma renin activity and angiotensin II to detection limit levels. The effects of aliskiren on RAS components were best comparable to those of 150 mg VTP-27999. CONCLUSION: Maximum renal renin blockade in healthy, salt-depleted volunteers, requires aliskiren doses higher than 300 mg, but can be established with 300 mg VTP-27999. To what degree such maximal effects (exceeding those of angiotensin-converting enzyme inhibitors and AT1-receptor blockers) are required in patients with renal disease, given the potential detrimental effects of excessive RAS blockade, remains to be determined.

Impact of glycaemic control on the effect of direct renin inhibition in the AVOID study.

INTRODUCTION: Hyperglycaemia induces development and progression of microvascular complications in diabetes. A direct link between high glucose levels and intrarenal renin-angiotensin activation has been demonstrated. This post-hoc analysis assessed the influence of baseline glycaemic control on the reduction of albuminuria with aliskiren or placebo added to losartan in the Aliskiren in the EValuation of PrOteinuria In Diabetes (AVOID) study. MATERIALS AND METHODS: In AVOID, 599 patients with type 2 diabetes, hypertension and nephropathy received 6 months' aliskiren or placebo added to losartan 100 mg and optimal antihypertensive therapy. Changes in urinary albumin creatinine ratio at end of study were assessed by tertiles of baseline HbA(1c) levels. RESULTS: Patients were divided into tertiles of HbA(1c) (<7.1%, 7.1 to <8.4% and ≥8.4%). There were no differences between tertiles, except patients in the highest tertile group more frequently used insulin. The antiproteinuric effect of aliskiren was consistent across tertiles, with the largest effect in the highest tertile (HbA(1c) ≥8.4%). CONCLUSIONS: This post-hoc analysis of the AVOID study suggests that renin inhibition with aliskiren 300 mg once daily added to losartan 100 mg once daily plus optimal antihypertensive therapy provides reductions in urinary albumin creatinine ratio that are efficacious in all, but particularly in poorly controlled, diabetic patients.

Impact of aliskiren treatment on urinary aldosterone levels in patients with type 2 diabetes and nephropathy: an AVOID substudy.

INTRODUCTION: Aldosterone blockade reduces albuminuria in diabetic patients with chronic kidney disease (CKD), and improves prognosis in chronic heart failure. This study assessed the effects of direct renin inhibition with aliskiren in combination with losartan and optimal antihypertensive therapy on urinary aldosterone, plasma renin activity (PRA) and plasma renin concentration (PRC). MATERIALS AND METHODS: In the AVOID study, 599 patients with type 2 diabetes, hypertension and nephropathy received 6 months aliskiren (150 mg force titrated to 300 mg once daily after 3 months) or placebo added to losartan 100 mg and optimal antihypertensive therapy. Urinary aldosterone excretion, PRA and PRC were measured at baseline and after 24 weeks in a prespecified subset of 133 patients. RESULTS: Aliskiren added to losartan provided reductions from baseline in urinary aldosterone compared with adding placebo (-24% vs. -4%, p = 0.017) at week 24. There was no significant difference between the aliskiren and placebo groups in the proportion of patients with aldosterone breakthrough (aliskiren 35%, placebo 46%, p = 0.199). Aliskiren treatment reduced PRA by 90% at 24 weeks and increased PRC by 328%. CONCLUSIONS: Adding aliskiren to recommended renoprotective treatment with losartan and optimal antihypertensive therapy provided significant reductions in urinary aldosterone excretion which may attenuate decline in kidney function.

Habitual flavonoid intake and endothelial function in healthy humans.

OBJECTIVE: Endothelial function, as measured by noninvasive techniques, is known to vary widely within populations. Our study was designed to test the hypothesis that this variation is determined in large part by a person's habitual dietary intake of flavonoids. METHODS: This was an analytical study examining the relationship between endothelial function and dietary flavonoids in 19 healthy older adults (mean age 72 years). The study took place in the inpatient Clinical Research Center of the Brigham and Women's Hospital. Habitual flavonoid intake was assessed via a focused food frequency questionnaire. Endothelial function, measured as the reactive hyperemia response to 1 dose of flavonoid-rich cocoa, was recorded with a plethysmographic device via peripheral arterial tonometry (PAT). RESULTS: Background flavonoid intake and the reactive hyperemia PAT (RH-PAT) response were significantly correlated (r = 0.7, p = 0.001); subjects with higher habitual flavonoid intake showed a significantly greater RH-PAT response than did lower consumers. PAT response to cocoa was also significantly correlated with simultaneous flavanol concentration in the blood (r = 0.5, p = 0.03). CONCLUSION: Individual variation in endothelial function among healthy older people, measured as PAT response to flavonoid-rich cocoa, is highly dependent upon usual daily flavonoid consumption. These data raise the possibility that the consumption of fruits and vegetables dictates basal endothelial function, likely related to their flavonoid content and influence on nitric oxide.

Renal responses to three types of renin-angiotensin system blockers in patients with diabetes mellitus on a high-salt diet: a need for higher doses in diabetic patients?

OBJECTIVE: Activation of the renal renin-angiotensin system in patients with diabetes mellitus appears to contribute to the risk of nephropathy. Recently, it has been recognized than an elevation of prorenin in plasma also provides a strong indication of risk of nephropathy. This study was designed to examine renin-angiotensin system control mechanisms in the patient with diabetes mellitus. METHODS: We enrolled 43 individuals with type 2 diabetes mellitus. All individuals were on a high-salt diet to minimize the contribution of the systemic renin-angiotensin system. After an acute exposure to captopril (25 mg), they were randomized to treatment with either irbesartan (300 mg) or aliskiren (300 mg) for 2 weeks. RESULTS: All agents acutely lowered blood pressure and plasma aldosterone, and increased renal plasma flow and glomerular filtration rate. Yet, only captopril and aliskiren acutely increased plasma renin and decreased plasma angiotensin II, whereas irbesartan acutely affected neither renin nor angiotensin II. Plasma renin and angiotensin II subsequently did increase upon chronic irbesartan treatment. When given on day 14, irbesartan and aliskiren again induced the above hemodynamic, renal and adrenal effects, yet without significantly changing plasma renin. Irbesartan at that time did not affect plasma angiotensin II, whereas aliskiren lowered it to almost zero. CONCLUSION: The relative resistance of the renal renin response to acute (irbesartan) and chronic (irbesartan and aliskiren) renin-angiotensin system blockade supports the concept of an activated renal renin-angiotensin system in diabetes, particularly at the level of the juxtaglomerular cell, and implies that diabetic patients might require higher doses of renin-angiotensin system blockers to fully suppress the renal renin-angiotensin system.

Evaluation of a direct prorenin assay making use of a monoclonal antibody directed against residues 32-39 of the prosegment.

BACKGROUND: Prorenin is an early marker of microvascular complications in diabetes. However, it can only be measured indirectly (following its conversion to renin), with a renin immunoradiometric assay (IRMA). Unfortunately, treatment with a renin inhibitor interferes with this assay, because renin inhibitors induce a conformational change in prorenin, thereby allowing its detection as renin. METHODS: We evaluated Molecular Innovation's new direct prorenin ELISA, which makes use of an antibody that recognizes an epitope near prorenin's putative cleavage site (R 43 L 44), thus no longer requiring prorenin activation. Plasma samples of 41 diabetic individuals treated with aliskiren (renin inhibitor) or irbesartan were tested. Semi-purified recombinant prorenin was used as standard, because the ELISA standard yielded approximately 10-fold lower values in the renin IRMA following its conversion to renin. RESULTS: The ELISA detected prorenin levels that were identical to those determined by the IRMA in untreated and irbesartan-treated individuals. Yet, it yielded higher prorenin levels in aliskiren-treated individuals. Aliskiren, at levels reached in plasma during treatment, did not interfere with the ELISA, but allowed the detection of up to 20-30% of prorenin as renin in the IRMA, thereby resulting in a significant overestimation of renin and an underestimation of prorenin. The ELISA rendered results within 2 h and did not require a pretreatment period of several days to convert prorenin to renin. CONCLUSION: The new direct assay allows rapid prorenin detection, is not hampered by aliskiren when used at clinically relevant doses, and might be used to identify diabetic patients developing retinopathy and/or nephropathy.

Varying patterns of the antihypertensive and antialbuminuric response to higher doses of renin-angiotensin-aldosterone system blockade in albuminuric hypertensive type 2 diabetes mellitus patients.

OBJECTIVE: In patients with type 2 diabetes mellitus (T2DM), blocking of the renin-angiotensin-aldosterone system (RAAS) has demonstrated efficacy in lowering blood pressure (BP) and urinary albumin excretion rate (UAER). Nonetheless, not all patients successfully respond to RAAS blockade with a reduction in BP and UAER. METHODS: This secondary analysis of a double-blind study of 391 patients with T2DM assessed the importance of using higher doses of the RAAS blocker valsartan to improve the BP and UAER response in patients initially identified as prompt or delayed responders. All patients received a starting dose of valsartan 160 mg for a 4-week run-in period to classify them as either prompt responders (SBP < 130 mmHg or reduction in SBP ≥10 mmHg, 53%) or delayed responders (47%). All patients were then subsequently randomized to one of three valsartan doses: 160, 320, or 640 mg/day for 26 weeks. RESULTS: Higher doses of valsartan (640 mg) demonstrated additional reductions in SBP among the prompt responders and led to greater SBP reductions from baseline (19.8 mmHg) compared with valsartan 160 (14.4 mmHg, P < 0.05) and 320 mg (16.5 mmHg). Among delayed responders, SBP reductions from baseline to end of study were similar (11-14 mmHg, P > 0.05) across all valsartan doses. For UAER, higher valsartan doses produced further reductions by week 30, regardless of initial response. CONCLUSION: Higher doses of valsartan did not appear to recruit delayed responders, but enhanced the prompt responder effects in patients with T2DM. Not all patients successfully respond in concordance to RAAS blockade with both reductions in BP and UAER. Reduction in BP dominates the antialbuminuric effect in both valsartan prompt responders and delayed responders independent of dose.

Aliskiren in combination with losartan reduces albuminuria independent of baseline blood pressure in patients with type 2 diabetes and nephropathy.

BACKGROUND AND OBJECTIVES: Elevated BP contributes to development and progression of proteinuria and decline in renal function in patients with type 2 diabetes. Our post hoc analysis assessed the baseline BP influence on the antiproteinuric effect in the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the AVOID study, 599 hypertensive type 2 diabetic patients with nephropathy received 6 months of aliskiren (150 mg force titrated to 300 mg daily after 3 months) or placebo added to losartan (100 mg) daily and optimal antihypertensive therapy. Changes in early morning urinary albumin:creatinine ratio and eGFR at week 24 were assessed by subgroups of baseline BP: Group A (prespecified target), <130/80 mmHg (n=159); Group B, <140/90 mmHg but ≥130/80 mmHg (n=189); and Group C (insufficient BP control), ≥140/90 mmHg (n=251). RESULTS: Mean baseline BP (mmHg) levels for Groups A, B, and C were 120/71, 133/78, and 145/81, respectively. BP during the trial was nearly identical to baseline levels in all groups. The antiproteinuric effects of aliskiren were consistent across subgroups of baseline BP (19 to 22% reduction versus placebo). In Group C, the decline in eGFR was significantly lower with aliskiren than with placebo (P=0.013). CONCLUSIONS: Aliskiren (300 mg) added to losartan (100 mg) plus optimal antihypertensive therapy provides antiproteinuric effects independent of BP in patients with type 2 diabetes and nephropathy. Renal function was better preserved with aliskiren in patients with insufficient BP control.

Impact of baseline renal function on the efficacy and safety of aliskiren added to losartan in patients with type 2 diabetes and nephropathy.

OBJECTIVE: Proteinuric diabetic patients with reduced glomerular filtration rate (GFR) are at high risk of renal and cardiovascular disease progression and treatment-related adverse events. This post hoc analysis assessed the efficacy and safety of aliskiren added to the maximal recommended dose of losartan according to baseline estimated GFR (eGFR) (stage 1-3 chronic kidney disease [CKD]). RESEARCH DESIGN AND METHODS: In the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study, 599 hypertensive patients with type 2 diabetes and nephropathy received 6 months of aliskiren (150 mg daily titrated to 300 mg daily after 3 months) or placebo added to 100 mg losartan and optimal antihypertensive therapy. Exclusion criteria included eGFR<30 ml/min per 1.73 m2 and serum potassium>5.1 mmol/l. RESULTS: Baseline characteristics were similar between treatment groups in all CKD stages. The antiproteinuric effects of aliskiren were consistent across CKD stages (19, 22, and 18% reduction). In the stage 3 CKD group, baseline serum creatinine levels were equal, but renal dysfunction, prespecified as a postrandomization serum creatinine elevation>176.8 µmol/l (2.0 mg/dl) occurred more frequently in the placebo group (29.2 vs. 13.6%, P=0.032). Serum potassium elevations>5.5 mmol/l (based on a single measurement) were more frequent with aliskiren (22.5 vs. 13.6%) in stage 3 CKD. Adverse event rates were similar between treatments, irrespective of CKD stage. CONCLUSIONS: Aliskiren added to losartan reduced albuminuria and renal dysfunction and was well tolerated, except for hyperkalemia (stage 3), independent of baseline CKD stage in patients with type 2 diabetes, hypertension, and nephropathy.

Brain blood flow and velocity: correlations between magnetic resonance imaging and transcranial Doppler sonography.

OBJECTIVE: Because transcranial Doppler sonography (TCD) is unable to measure arterial diameter, it remains unproven whether the changes in cerebral blood velocity it measures are representative of changes in cerebral blood flow (CBF). Our study was designed to compare velocity changes with flow changes measured by two magnetic resonance imaging (MRI) techniques, perfusion MRI and arterial spin labeling (ASL), using flavanol-rich cocoa to induce CBF changes in healthy volunteers. METHODS: We enrolled 20 healthy volunteers aged 62 to 80 years (mean, 73 years). Each was studied at baseline and after drinking standardized servings of cocoa for 7 to 14 days. RESULTS: Changes in middle cerebral artery (MCA) flow by TCD were significantly correlated with changes in perfusion assessed by gadolinium-enhanced MRI (r = 0.63; P < .03). Measurements with ASL showed a stronger correlation with borderline significance. CONCLUSIONS: Changes in flow velocity in the MCA associated with drinking cocoa were highly correlated with changes in CBF measured by the two MRI techniques using the tracer gadolinium and ASL. These results validate Doppler measurements of CBF velocity as representative assessments of CBF.

Direct renin inhibition and the kidney.

Direct renin inhibition is a new means for blocking the renin-angiotensin system at the rate-limiting step of the cascade of events triggered by renin release--the interaction of renin with its physiological substrate angiotensinogen. The remarkable success of angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers in the management of cardiovascular and renal disease has led to great interest in the potential of direct renin inhibitors. This Review focuses on the evidence that suggests that direct renin inhibitors might block the renin-angiotensin system in the kidney more completely than either angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers. The therapeutic implications of this evidence are also reviewed, as well as the possible mechanistic routes by which direct renin inhibition might exert its influence on the kidney.

Antihypertensive effects of double the maximum dose of valsartan in African-American patients with type 2 diabetes mellitus and albuminuria.

OBJECTIVE: The blood pressure (BP)-lowering response to renin-angiotensin-aldosterone system blockade in hypertensive African-Americans is typically less than in whites. To determine whether higher than conventional doses of renin-angiotensin-aldosterone system blockade can improve BP reduction in African-American patients. METHODS: Hypertensive patients with type 2 diabetes and albuminuria were enrolled: 110 African-Americans (BP = 150/87 mmHg, aged 57.5 +/- 11 years) and 281 non-African-Americans (BP = 151/89 mmHg, aged 57.7 +/- 11 years). All patients received valsartan 160 mg once daily in the morning for 4 weeks, following which patients were randomized to receive one of three valsartan doses: 160, 320 or 640 mg/day (2x, maximal recommended dose) for 26 weeks. If at week 6, target BP (<130/80 mmHg) was not achieved, then other add-on antihypertensives were allowed. RESULTS: The predominant BP (DeltaSBP/DeltaDBP) reduction was observed within 4 weeks and was lesser in African-Americans (7.8 +/- 15/4.5 +/- 9 mmHg) than non-African-Americans (8.9 +/- 14/6.6 +/- 1 mmHg, P < 0.05). Greater reduction in urinary albumin excretion was observed with higher doses (320 or 640 mg); however, the responses were similar between African-Americans and non-African-Americans. Use of add-on antihypertensives was higher in African-American (56%) vs. non-African-American patients (36%) with a similar rate across the three valsartan doses. From week 4-26, reduction in BP was lesser (P < 0.05) for African-American than non-African-American patients at the160-mg dose but not with 320 and 640-mg doses. CONCLUSION: In African-American patients, a lower BP reduction response was observed to conventional doses of valsartan than non-African-American patients, but at 640 mg, a higher response was observed in African-American patients than in non-African-American patients.

A comparison of prediction equations for estimating glomerular filtration rate in pregnancy.

OBJECTIVE: To compare existing glomerular filtration rate (GFR) prediction equations with the gold standard, inulin clearance, in pregnancy. METHODS: Five equations were assessed for precision, bias, and accuracy in prediction of true GFR, measured by inulin clearance in 12 healthy, pregnant women during the second (T2) and third (T3) trimesters and in postpartum (PP). RESULTS: Precision was greatest with 24-hour creatinine clearance estimation of GFR (R(2) = 13% (T2), R(2) = 26% (T3)). Other than 100/SCr, all equations underestimated true GFR. 30% accuracy was greatest in 100/SCr (83% (T2), 92% (T3)). CONCLUSIONS: Current GFR prediction formulae do not appear to be sufficient for estimating GFR in the gravid state.

Cocoa and cardiovascular health.

Epidemiological data demonstrate that regular dietary intake of plant-derived foods and beverages reduces the risk of coronary heart disease and stroke. Among many ingredients, cocoa might be an important mediator. Indeed, recent research demonstrates a beneficial effect of cocoa on blood pressure, insulin resistance, and vascular and platelet function. Although still debated, a range of potential mechanisms through which cocoa might exert its benefits on cardiovascular health have been proposed, including activation of nitric oxide and antioxidant and antiinflammatory effects. This review summarizes the available data on the cardiovascular effects of cocoa, outlines potential mechanisms involved in the response to cocoa, and highlights the potential clinical implications associated with its consumption.

[Aliskiren combined with losartan in type 2-diabetes and nephropathy - secondary publication]. / Kombination af aliskiren og losartan hos patienter med type 2-diabetes og nefropati - Sekundaerpublikation.

We evaluated the renoprotective effects of adding aliskiren to treatment with losartan in hypertensive patients with type 2 diabetes and nephropathy. A total of 599 patients were randomized to six months of treatment with placebo or aliskiren in addition to losartan 100 mg and optimal antihypertensive therapy. The primary outcome was a reduction in the urinary albumin-creatinine ratio. Aliskiren 300 mg daily reduced the mean urinary albumin-creatinine ratio by 20% (p < 0.001) compared with placebo. The number of adverse events was similar between groups. Aliskiren is renoprotective independently of its blood pressure lowering effect.

Flavanols, the Kuna, cocoa consumption, and nitric oxide.

The Kuna Indians, who reside in an archipelago on the Caribbean Coast of Panama, have very low blood pressure (BP) levels, live longer than other Panamanians, and have a reduced frequency of myocardial infarction, stroke, diabetes mellitus, and cancer-at least on their death certificates. One outstanding feature of their diet includes a very high intake of flavanol-rich cocoa. Flavonoids in cocoa activate nitric oxide synthesis in healthy humans. The possibility that the high flavanol intake protects the Kuna against high BP, ischemic heart disease, stroke, diabetes mellitus, and cancer is sufficiently intriguing and sufficiently important that large, randomized controlled clinical trials should be pursued.

Renal plasma flow: glomerular filtration rate relationships in man during direct renin inhibition with aliskiren.

We examined the relation between change in renal plasma flow (RPF) and change in glomerular filtration rate (GFR) in healthy humans on a low-salt diet during direct renin inhibition with aliskiren. We measured the renal hemodynamic response to acute dosing of 300mg aliskiren by mouth to 19 healthy normotensive subjects (age, 33+/-3 years; baseline RPF, 575+/-23; GFR, 138+/-14mL/min/1.73m(2)) on a low-sodium diet (10mmol/day). GFR and RPF were measured by the clearance of inulin and para-aminohippurate. There was a marked increase in average RPF (169+/-24mL/min/1.73m(2)) and a small rise in average GFR (1.4+/-5mL/min/1.73m(2)) from baseline in response to aliskiren. There was a clear correlation between the change in RPF and the change in GFR between subjects (r=0.65; P < .003). A substantial increase in RPF was accompanied by a rise in GFR. Dependence of GFR on RPF was identified in healthy humans after RPF rose significantly with aliskiren. The responsible mechanism likely involves intravascular oncotic pressure along the glomerular capillary resulting in greater surface area available for filtration.

Aliskiren accumulates in Renin secretory granules and binds plasma prorenin.

The vascular effects of aliskiren last longer than expected based on its half life, and this renin inhibitor has been reported to cause a greater renin rise than other renin-angiotensin system blockers. To investigate whether aliskiren accumulation in secretory granules contributes to these phenomena, renin-synthesizing mast cells were incubated with aliskiren, washed, and exposed to forskolin in medium without aliskiren (0.1 to 1000 nmol/L). (Pro)renin concentrations were measured by renin- and prorenin-specific immunoradiometric assays, and renin activity was measured by enzyme-kinetic assay. Without aliskiren, the culture medium predominantly contained prorenin, the cells exclusively stored renin, and forskolin doubled renin release. Aliskiren dose-dependently bound to (pro)renin in the medium and cell lysates and did not alter the effect of forskolin. The aliskiren concentrations required to bind prorenin were 1 to 2 orders of magnitude higher than those needed to bind renin. Blockade of cell lysate renin activity ranged from 27+/-15% to 79+/-5%, and these percentages were identical for the renin that was released by forskolin, indicating that they represented the same renin pool, ie, the renin storage granules. Comparison of renin and prorenin measurements in blood samples obtained from human volunteers treated with aliskiren, both before and after prorenin activation, revealed that