***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The effects of sustained renin inhibition by repeated administration of enalkiren ( A- 64662 ) , the novel dipeptide renin inhibitor , were evaluated in a r and omized , double-blind , placebocontrolled , parallel-group study of 32 in patients ( eight per group ) with essential hypertension who were maintained on a diet containing 60 meq/day sodium . Three different dosage regimens of enalkiren were studied : 1 ) 1.2 mg/kg quotid . , 2 ) 03 mg/kg q.i.d . , and 3 ) 0.1 mg/kg q.i.d . Each patient received an intravenous infusion every 6 hours for 1 week . Placebo infusions were used to mimic the 4 times/day dosing schedule . Blood pressure was measured periodically via 24-hour automated monitoring equipment . Mean plasma renin activity in the patient groups ranged from 1.58 to 2.68 ng angiotensin I/ml/hr . Plasma renin activity was promptly suppressed in all groups receiving enalkiren . Prolonged duration of plasma renin activity suppression ( ≥24 hours ) was demonstrated after the administration of 1.2 mg/kg enalkiren . The 0 3 mg/kg q.i.d . and 1.2 mg/kg quotid . regimens produced statistically significant reductions ( p < 0.05 ) in systolic and diastolic blood pressures with clear evidence of persistent antihypertensive activity for 12 hours or more when compared with the placebo group . Despite relatively large reductions in mean systolic and diastolic blood pressure , mean pulse rates were essentially unchanged . The prolonged reduction in blood pressure  with enalkiren without evidence of tachyphylaxis after 1 week of treatment suggests that renin inhibitors may emerge as useful therapeutic agents for the treatment of hypertension Aliskiren is a novel orally active renin inhibitor for the treatment of hypertension . This study evaluated the antihypertensive efficacy , safety and tolerability of aliskiren in Japanese patients with hypertension . Forty hundred and fifty-five Japanese men and women with a mean sitting diastolic blood pressure of 95–110 mmHg were r and omized to receive once-daily double-blind treatment for 8 weeks with aliskiren 75 , 150 or 300 mg or placebo . Aliskiren produced significant , dose-dependent reductions in mean sitting diastolic blood pressure ( p<0.0005 vs. placebo for each dose ) and mean sitting systolic blood pressure ( p<0.001 vs. placebo for each dose ) . The placebo-corrected reductions in mean sitting systolic/diastolic blood pressure were 5.7/4.0 , 5.9/4.5 and 11.2/7.5 mmHg in the aliskiren 75 , 150 and 300 mg groups , respectively . After 8 weeks ' treatment , 27.8 % , 47.8 % , 48.2 % and 63.7 % of patients in the placebo and aliskiren 75 , 150 and 300 mg groups , respectively , achieved a successful treatment response ( diastolic blood pressure < 90 mmHg and /or reduced by ≥10 mmHg from baseline ; p<0.005 vs. placebo for each dose ) . Aliskiren treatment was well tolerated , with the incidence of adverse events reported in the active treatment groups ( 53–55 % ) being similar to that in the placebo group ( 50 % ) . This study , which is the first to assess the antihypertensive efficacy and safety  of aliskiren in Japanese patients with hypertension , demonstrates that the once-daily oral renin inhibitor aliskiren provides significant , dose-dependent reductions in blood pressure with placebo-like tolerability BACKGROUND Patients with type 2 diabetes are at increased risk of macro- and microvascular disease , and the presence of albuminuria and /or reduced kidney function further enhances macrovascular risk . Angiotensin-converting-enzyme inhibitors reduce both macro- and microvascular events , yet the residual renal and cardiovascular risk still remains high . Aliskiren a novel oral direct renin inhibitor that unlike ACEi and ARBs , lowers plasma renin activity , angiotensin I and angiotensin II levels , may thereby provide greater benefit compared to ACEi or ARB alone . METHODS The primary objective of the ALTITUDE trial is to determine whether aliskiren 300 mg once daily , reduces cardiovascular and renal morbidity and mortality compared with placebo when added to conventional treatment ( including ACEi or ARB ) . ALTITUDE is an international , r and omized , double-blind , placebo-controlled , parallel-group study , which will include three categories of high-risk patients with type 2 diabetes ( aged > or = 35 years ) : those with either urinary albumin/creatinine ratio ( UACR ) > or = 200 mg/g ; microalbuminuria ( UACR ) > or = 20 < 200 mg/g and eGFR > or = 30 < 60 mL/min/1.73 m2 ; and thirdly , those with a history of cardiovascular disease and eGFR > or = 30 < 60 mL/min/1.73 m2 with or without microalbuminuria . ALTITUDE is an event driven trial that aims to r and omize 8600 patients with a planned follow-up time of 48 months . The primary outcome measure is time to first event for the composite endpoint of cardiovascular death , resuscitated death , myocardial infa rct ion , stroke , unplanned hospitalization for heart failure , onset of end-stage renal disease or doubling of baseline serum creatinine concentration . Secondary endpoints include a composite CV endpoint and a composite renal endpoint . CONCLUSION ALTITUDE will determine whether dual RAAS blockade with the direct renin inhibitor aliskiren in combination with an ACEi or ARB will reduce major morbidity and mortality in a broad range of high-risk patients with type 2 diabetes BACKGROUND Remikiren is an orally active renin inhibitor with established antihypertensive efficacy . As a single dose it induces renal vasodilatation , suggesting specific renal actions . Data on the renal effects of continued treatment by renin inhibition are not available , either in subjects with normal , or in subjects with impaired renal function . METHODS The effect of 8 days of treatment with remikiren 600 mg o.i.d . on blood pressure , renal haemodynamics , and proteinuria was studied in 14 hypertensive patients with normal or impaired renal function . The study was conducted on an ambulatory in-hospital basis and was design ed in a single-blind , longitudinal order . RESULTS Remikiren induced a significant peak fall in mean arterial pressure of 11.2+/-0.8 % , with corresponding trough values of -6+/-0.8 % . This fall was somewhat more pronounced in the patients with renal function impairment ( -13.3 vs -9.6 % ; P<0.01 ) . Glomerular filtration rate remained stable , whereas effective renal plasma flow increased from 301+/-35 to 330+/-36 ml/min/1.73 m(2 ) ( P<0.05 ) . Filtration fraction and renal vascular resistance fell by 10+/-2 % and 15+/-2 % respectively ( both P<0.01 ) . Remikiren induced a cumulated sodium loss of -82+/-22 mmol and a positive potassium balance of 49+/-9 mmol ( both P<0.01 ) . During remikiren , proteinuria fell by 27 % ( range -18 to -38 % ; P<0.01 ) in the patients with overt proteinuria at onset ( n=6 ) . In the remainder of the patients albuminuria fell by 20 % ( range -1 to -61 % , P<0.05 ) . No side-effects were observed . CONCLUSIONS Continued treatment with remikiren induced a sustained fall in blood pressure , renal vasodilatation , negative sodium balance , and a reduction in glomerular protein leakage . These data are consistent with a renoprotective potential of renin inhibition Background — Diuretics are recommended as first-line agents for the treatment of hypertension . This r and omized , double-blind , multicenter study assessed the long-term efficacy and safety of the direct renin inhibitor aliskiren in comparison with the diuretic hydrochlorothiazide in patients with essential hypertension . Methods and Results — After a 2- to 4-week placebo run-in , 1124 patients ( mean sitting diastolic blood pressure [ BP ] 95 to 109 mm Hg ) were r and omized to aliskiren 150 mg ( n=459 ) , hydrochlorothiazide 12.5 mg ( n=444 ) , or placebo ( n=221 ) once daily . Forced titration ( to aliskiren 300 mg or hydrochlorothiazide 25 mg ) occurred at week 3 ; at week 6 , patients receiving placebo were reassigned ( 1:1 ratio ) to aliskiren 300 mg or hydrochlorothiazide 25 mg . From week 12 , amlodipine 5 mg was added and titrated to 10 mg from week 18 for patients whose BP remained uncontrolled . Efficacy variables were analyzed for the intent-to-treat population with the use of the last observation carried forward method . BP reductions ( mean sitting systolic BP/mean sitting diastolic BP ) were significantly greater with aliskiren- versus hydrochlorothiazide-based treatment at week 26 ( −20.3/−14.2 versus −18.6/−13.0 mm Hg ; P<0.05 ) and were also greater at week 52 ( −22.1/−16.0 versus −21.2/−15.0 mm Hg ; P<0.05 for mean sitting diastolic BP ) . At the end of the monotherapy period ( week 12 ) , aliskiren 300 mg was superior to hydrochlorothiazide 25 mg in reducing BP ( −17.4/−12.2 versus −14.7/−10.3 mm H ; P<0.001 ) . Adverse event rates were similar with aliskiren- ( 65.2 % ) and hydrochlorothiazide-based therapy ( 61.5 % ) . Hypokalemia was more frequent with hydrochlorothiazide-based therapy than aliskiren-based therapy ( 17.9 % versus 0.9 % ; P<0.0001 ) . Conclusions — Aliskiren treatment , both as monotherapy and with optional addition of amlodipine , provided significantly greater BP reductions than the respective hydrochlorothiazide regimens . Aliskiren-based therapy was well tolerated . Direct renin inhibition with aliskiren therefore represents an effective option for the long-term treatment of essential hypertension BACKGROUND Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries . We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren , an oral direct renin inhibitor , to treatment with the maximal recommended dose of losartan ( 100 mg daily ) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy . METHODS We enrolled 599 patients in this multinational , r and omized , double-blind study . After a 3-month , open-label , run-in period during which patients received 100 mg of losartan daily , patients were r and omly assigned to receive 6 months of treatment with aliskiren ( 150 mg daily for 3 months , followed by an increase in dosage to 300 mg daily for another 3 months ) or placebo , in addition to losartan . The primary outcome was a reduction in the ratio of albumin to creatinine , as measured in an early-morning urine sample , at 6 months . RESULTS The baseline characteristics of the two groups were similar . Treatment with 300 mg of aliskiren daily , as compared with placebo , reduced the mean urinary albumin-to-creatinine ratio by 20 % ( 95 % confidence interval , 9 to 30 ; P<0.001 ) , with a reduction of 50 % or more in 24.7 % of the patients who received aliskiren as compared with 12.5 % of those who received placebo ( P<0.001 ) . A small difference in blood pressure was seen between the treatment groups by the end of the study period ( systolic , 2 mm Hg lower [ P=0.07 ] and diastolic , 1 mm Hg lower [ P=0.08 ] in the aliskiren group ) . The total numbers of adverse and serious adverse events were similar in the groups . CONCLUSIONS Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension , type 2 diabetes , and nephropathy who are receiving the recommended renoprotective treatment . ( Clinical Trials.gov number , NCT00097955 [ Clinical Trials.gov ] . ) Background —Loss of negative feedback inhibition of renin release during chronic treatment with an angiotensin-converting enzyme ( ACE ) inhib 
    Output:
    
Blood pressure reductions were generally insufficient using early generation DRIs .
However , recent DRIs have greater blood pressure-lowering effects .
Pre clinical and clinical studies showed profound effects of DRIs on markers of renal function , including clear increases in renal plasma flow and reductions in albuminuria .
These effects were observed either alone or in combination with other RAAS inhibitors and suggest potential large renal protective benefit .
DRIs improved hemodynamic cardiovascular parameters , such as total peripheral resistance , arterial pressure and left ventricular mass index , to a similar extent as those observed with other RAAS inhibitors .
Furthermore , addition of DRIs to optimal heart failure treatment result ed in further reductions in B-type natriuretic peptide .
CONCLUSIONS Evidence from pre clinical and clinical studies suggests that DRIs may have renal and cardiovascular effects beyond their ability to lower blood pressure .