***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: BACKGROUND We evaluated the renoprotective effects of dual blockade of renin-angiotensin system ( RAS ) by using a low-dose combination of ACE inhibiter and angiotensin II receptor blocker in type 2 diabetic patients with advanced kidney disease . The amount of proteinuria and the urinary levels of bioassayable TGF-beta1 were used as surrogate markers of renal injury and sclerosis . METHODS We performed a prospect i ve double-blinded r and omized crossover trial consisting of three 16-week treatment periods with ramipril alone ( 10 mg/day ) , c and esartan alone ( 16 mg/day ) , and ramipril ( 5 mg/day ) plus c and esartan ( 8 mg/day ) combination therapy .  Twenty-one type 2 diabetic patients with overt nephropathy with a 24 h urinary protein excretion rate ( UPER ) of > 1.0 g/24 h and creatinine clearance ( Ccr ) of 30 to 59 ml/min/1.73 m2 completed the entire study . RESULTS Subjects consisted of 10 female and 11 male patients with a mean age of 49 + /- 8 years and duration of diabetes ranging from 4 to 13 years . At baseline , 24-h blood pressures ( BPs ) were 133 + /- 6/81 + /- 7 mmHg , Ccr 40.6 + /- 4.1 ml/min/1.73 m2 , 24-h UPER 4.1 + /- 1.9 g/24 h , and urinary TGF-beta1 level 28.4 + /- 16.1 pg/mg creatinine ( cr ) . Although there was no comparable change in BP and plasma/urinary biochemical parameters , 24-h UPER was significantly reduced by the combination therapy ( 2.9 + /- 1.4 g/24 h ) compared with that of ramipril ( 3.5 + /- 1.8 g/24 h ) and of c and esartan ( 3.3 + /- 2.0 g/24 h ) single therapy ( P < 0.05 ) . Urinary TGF-beta1 level was reduced in all three therapies compared with that of the control ( 28.4 + /- 16.1 pg/mg cr ) ( P < 0.05 ) . However , the combination therapy showed the most significant change ( combination 19.6 + /- 10.6 pg/mg cr ; ramipril 24.7 + /- 13.3 pg/mg cr ; c and esartan ; 23.4 + /- 11.7 pg/mg cr ) . No significant or irreversible adverse effect was observed in the 21 patients who completed the entire study . CONCLUSIONS The dual blockade of RAS with low-dose ramipril plus c and esartan was found to be safe and offered additive benefits with respect to reducing proteinuria and urinary TGF-beta1 excretion in diabetic patients with advanced kidney disease . These benefits were evident as compared with single ramipril and c and esartan therapies at doses two-fold greater . Further study on the dose-titration is m and atory in terms of safety and especially for maximizing renoprotection in this patient population Combination therapy with angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors ( ACEIs ) requires further evaluation in patients with diabetic nephropathy and hypertension . In a post hoc analysis of the Olmesartan Reducing Incidence of Endstage renal disease in diabetic Nephropathy Trial with hypertension , we examined the effects of olmesartan on renal and cardiovascular outcomes in the presence or absence of an ACEI . Among 563 patients r and omized to receive either olmesartan ( n=280 ) or placebo ( n=283 ) , 73.5 % ( n=414 ) received a concomitant ACEI . Compared with placebo , olmesartan significantly reduced proteinuria in both the ACEI-treated and non-ACEI-treated groups . The respective changes in the urinary protein creatinine ratio in the olmesartan-treated and placebo-treated groups were −32.6 % and + 21.1 % without an ACEI ( P=0.001 ) and −17.0 % and + 2.2 % with an ACEI ( P=0.028 ) . In the olmesartan group , 115 patients developed primary renal outcomes ( 41.1 % ) compared with 129 ( 45.6 % ) in the placebo group ( hazard ratio ( HR ) : 0.97 , P=0.787 ) . The respective HRs in the ACEI-treated and non-ACEI-treated groups were 1.02 ( P=0.891 ) and 0.84 ( P=0.450 ) . 40 olmesartan-treated patients ( 14.3 % ) and 53 placebo-treated patients ( 18.7 % ) developed secondary cardiovascular outcomes ( HR : 0.65 , P=0.042 ) . The respective HRs in the ACEI-treated and non-ACEI-treated groups were 0.69 ( P=0.129 ) and 0.51 ( P=0.129 ) . Olmesartan was well tolerated . Dual blockade treatment caused more hyperkalemia than monotherapy . In patients with diabetic nephropathy and hypertension  , olmesartan significantly reduced proteinuria , independent of ACEI treatment and cardiovascular outcome but failed to show additional renal benefit compared with ACEI treatment alone . The cardiovascular benefit of dual treatment requires further evaluation Angiotensin-converting enzyme ( ACE ) inhibitors have favourable effects on hypertension and diabetic nephropathy , but persistent use may result in incomplete blockade of the renin-angiotensin system . Long-term effects of dual blockade using the ACE inhibitor lisinopril and the long-acting angiotensin II receptor blocker ( ARB ) telmisartan on blood pressure and albumin excretion rate ( AER ) were evaluated . Patients with type 2 diabetes mellitus , hypertension ( systolic blood pressure [ SBP ] > or=140 mmHg or diastolic blood pressure [ DBP ] > or=90 mmHg ) and microalbuminuria ( AER 30 - 300 mg/24h ) received 20 mg of lisinopril or 80 mg of telmisartan once a day for 24 weeks . Patients were then r and omised to continuing treatment with the respective monotherapy or with lisinopril plus telmisartan for a further 28 weeks . Significant ( P<0.001 ) declines in SBP ( 11.1 mmHg versus 10.0 mmHg ) , DBP ( 5.6 mmHg versus 5.3 mmHg ) and AER ( 98 mg/24 h versus 80 mg/24 h ) were achieved with lisinopril ( n=95 ) or telmisartan ( n=97 ) , respectively , after 24 weeks . Subsequent treatment with lisinopril plus telmisartan for 28 weeks result ed in further significant reductions ( P<0.001 ) in SBP , DBP and AER compared with either monotherapy . All treatments were well tolerated . Lisinopril plus telmisartan thus provides superior blood pressure and AER control than either monotherapy . We conclude that use of dual blockade may provide a new approach to prevention of diabetic nephropathy in patients with type 2 diabetes , hypertension and microalbuminuria BACKGROUND Angiotensin-converting enzyme ( ACE ) inhibitors or angiotensin II receptor blockers ( ARB ) have been shown to delay the progression to proteinuria and kidney failure in hypertensive type 2 diabetic patients with diabetic nephropathy . Further synergistic effect may be obtained by combined therapy with both ARB and ACE inhibitors . OBJECTIVE To evaluate the effect of dual blockage of the renin-angiotensin system by adding maximal recommended dose of ARB with maximal recommended dose of ACE inhibitors in type 2 diabetic patients with diabetic nephropathy . MATERIAL AND METHOD Type 2 diabetic patients with urine protein/creatinine ( UPCr ) > 0.5 gm/gm and hypertension who received maximal recommended dose of ACE inhibitors ( Enalapril 40 mg/day ) over three months were r and omized to two groups .  ARB group received adding maximal recommended dose of ARB ( Telmisartan 80 mg/day ) and control group received previous ACE inhibitors only for 24 weeks . RESULTS Eighty patients were enrolled . ARB group led to significantly reduced UPCr from baseline at week 8 , 12 , and 24 ( 2.65 + /- 1.81 , 2.24 + /- 1.85 , 2.24 + /- 1.88 and 1.98 + /- 1.73 gm/gm respectively , p < 0.05 ) but UPCr in the control group was unchanged ( 1.97 + /- 1.56 , 1.85 + /- 1.27 , 1.97 + /- 1.11 and 1.96 + /- 1.42 gm/gm respectively , p > 0.05 ) . ARB group induced an additional reduction in proteinuria of 29.25 % ( 95 % CI 9.68 - 48.82 ) compared with control group . By the end of the present study , glomerular filtration rate had fallen from 41.76 + /- 12.16 to 37.84 + /- 13.59 ml/min/1.73 m2 in ARB group and 50.89 + /- 29.43 to 49.41 + /- 29.85 ml/min/1.73 m2 in control group ( p > 0.05 ) . Serum potassium had changed from 4.51 + /- 0.48 to 4.58 + /- 0.13 mEq/L in ARB group and 4.60 + /- 0.58 to 4.40 + /- 0.13 mEq/L in the control group ( p > 0.05 ) . No other serious adverse effects were reported during treatment . CONCLUSION Adding maximal recommended dose of ARB with maximal recommended dose of ACE inhibitors in type 2 diabetic patients can reduce proteinuria more than ACE inhibitors alone . This treatment is safe and well tolerated BACKGROUND Aldosterone has been suggested to play a role in the initiation and progression of diabetic nephropathy . Currently recommended treatment with angiotensin-converting enzyme ( ACE ) inhibitors or angiotensin II receptor blockers [ renin-angiotensin system ( RAS ) blockade ] does not suppress circulating aldosterone sufficiently . We therefore aim ed to evaluate the short-term effect of aldosterone antagonism with spironolactone on albuminuria and blood pressure in diabetic nephropathy . METHODS Twenty Caucasian type 1 diabetic patients with persistent macroalbuminuria despite antihypertensive treatment , including RAS blockade , completed this double-masked , r and omized cross-over trial . Patients were treated in r and om order with spironolactone 25 mg once daily and matched placebo for two months , respectively , on top of usual antihypertensive treatment . After each treatment period albuminuria , 24-hour blood pressure , and glomerular filtration rate ( GFR ) were determined . RESULTS Spironolactone on top of usual antihypertensive treatment induced a 30 % ( 95 % CI 17 to 41 ) reduction in albuminuria from [ geometric mean ( 95 % CI ) ] 831 ( 624 to 1106 ) mg/24-hour on placebo treatment ( P < 0.001 ) , and a reduction in fractional albumin clearance of 35 % ( 20 to 46 , P < 0.001 ) . Twenty-four-hour blood pressure showed an insignificant reduction of [ mean reduction ( 95 % CI ) ] 8 ( -1 to 17)/3 ( -0.2 to 7 ) mm Hg ( P < 0.10 ) . There was an insignificant reversible reduction in GFR during treatment with spironolactone . On spironolactone treatment , one patient was excluded due to  hyperkalemia  ( plasma potassium 5.7 mmol/L ) and one due to orthostatic dizziness . Otherwise treatment was well tolerated . CONCLUSION Our results suggest that spironolactone treatment on top of recommended antihypertensive treatment reduces blood pressure and may offer additional renoprotection in type 1 diabetic patients with diabetic nephropathy Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients . This study tested whether dual blockade of the renin-angiotensin system ( RAS ) with both an angiotensin-converting enzyme ( ACE ) inhibitor ( ACE-I ) and an Angiotensin-II receptor blocker ( ARB ) is superior to either drug alone in type I diabetic patients with diabetic nephropathy ( DN ) . A r and omized double-blind crossover trial was performed with  
    Output:
    
Results Based on 42 RCTs with 14,576 patients , dual RAAS blockade therapy was associated with significant decreases in blood pressure , albuminuria , and proteinuria .
However , dual therapy was not superior to monotherapy in terms of reductions in all-cause mortality , cardiovascular mortality , or progression to end-stage renal disease ( ESRD ) .
Significant increases in serum potassium and rates of hyperkalemia and hypotension were more common in patients treated with dual therapy .
However , glomerular filtration rates ( GFR ) did not decrease significantly with dual therapy .
The risk of hyperkalemia increased significantly in patients with DKD with macroalbuminuria but not in those with microalbuminuria .
Conclusion Dual inhibition therapy is superior to monotherapy for blood pressure control and urine protein reduction , though such superiority does not translate into improvements in longer-term outcomes , such as reduced progression to ESRD , all-cause mortality , and cardiovascular mortality .
An ACEI plus an ARB or a DRI plus an ACEI/ARB may be a safe and effective therapy for patients with DKD , and combination therapy may be suitable for patients with DKD and hypertension and microalbuminuria