***TASK*** the task is to summarize an input biomedical literature in six sentences 
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    Input: BACKGROUND Few studies have directly compared the renoprotective effects of angiotensin II-receptor blockers and angiotensin-converting-enzyme ( ACE ) inhibitors in persons with type 2 diabetes . METHODS In this prospect i ve , multicenter , double-blind , five-year study , we r and omly assigned 250 subjects with type 2 diabetes and early nephropathy to receive either the angiotensin II-receptor blocker telmisartan ( 80 mg daily , in 120 subjects ) or the ACE inhibitor enalapril ( 20 mg daily , in 130 subjects ) . The primary end point was the change in the glomerular filtration rate ( determined by measuring the plasma clearance of iohexol ) between the baseline value and the last available value during the five-year treatment period . Secondary end points included the annual changes in the glomerular filtration rate , serum creatinine level , urinary albumin excretion , and blood pressure ; the rates of end-stage renal disease and cardiovascular events ; and the rate of death from all causes . RESULTS After five years , the change in the glomerular filtration rate was -17.5 ml per minute per 1.73 m2 ( where the minus sign denotes a decrement ) in the telmisartan-treated subjects , as compared with -15.0 ml per minute per 1.73 m2 in the enalapril-treated subjects ; the treatment difference was thus -2.6 ml per minute per 1.73 m2 ( 95 percent confidence interval , -7.1 to 2.0 ml per minute per 1.73 m2)[corrected ] The lower boundary of the confidence interval , in favor of enalapril , was greater than the predefined margin of -10.0 ml per minute per 1.73 m2 , indicating that telmisartan was not inferior to enalapril . The effects of the two agents on the secondary end points were not significantly different after five years . CONCLUSIONS Telmisartan is not inferior to enalapril in providing long-term renoprotection in persons with type 2 diabetes . These findings do not necessarily apply to persons with more advanced nephropathy , but they support the clinical equivalence of angiotensin II-receptor blockers and ACE inhibitors in persons with conditions that place them at high risk for cardiovascular events We tested the hypothesis that blockade of angiotensin II type 1 receptors reduces oxidative stress markers in parallel with urinary albumin and type IV collagen excretions . Sixty-six diabetic patients with nephropathy were r and omly assigned to either the angiotensin II receptor blocker ( ARB ; n=33 ) or trichlormethiazide ( n=33 ) group . The majority of patients had been treated with angiotensin-converting enzyme inhibitors or calcium channel blockers for ≥1 year before the present study . Reduction of blood pressure was not different between the 2 groups , and HbA1c levels did not change over the study period ( 8 weeks ) . Treatment with ARB ( c and esartan 8 mg/day , n=11 or valsartan 80 mg/day , n=22 ) for 8 weeks reduced the levels of plasma monocyte chemoattractant protein 1 , interleukin 6 , urinary 8-epi-prostagl and in F2&agr ; , 8-hydroxydeoxyguanosine , albumin , and type IV collagen , whereas the levels of these markers were not altered with trichlormethiazide ( 2 mg/day ) . Significant correlation was observed between the reduction of the urinary 8-epi- prostagl and in F2&agr ; and 8-hydroxydeoxyguanosine and those of the urinary albumin and type IV collagen . Subjects with large oxidative stress had large reduction rates because of ARB administration and showed large urinary albumin suppression . These results suggest that ARBs  reduce oxidative stress and inflammation in diabetic patients independent of their effects on blood pressure . In addition , increases in oxidative stress caused by angiotensin II may play an important role in the progression of diabetic nephropathy . Our results may help to explain the clinical observation that ARB reduces urinary albumin excretion very efficiently in some patients but not in others Both angiotensin-converting enzyme inhibitors ( ACEIs ) and angiotensin receptor blockers ( ARBs ) can slow the progression of diabetic nephropathy . Even with ACEI or ARB treatment , the proportion of patients who progress to end-stage renal disease ( ESRD ) remains high . Interventions that achieve more complete blockade of the renin-angiotensin system , such as combination ACEI and ARB , might be beneficial . This approach may decrease progression of nondiabetic kidney disease . In diabetic nephropathy , combination therapy decreases proteinuria , but its effect in slowing progression is unknown . In addition , the potential for hyperkalemia may limit the utility of combined therapy in this population . VA NEPHRON-D is a r and omized , double-blind , multicenter clinical trial to assess the effect of combination losartan and lisinopril , compared with losartan alone , on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria . The primary endpoints are time to ( 1 ) reduction in estimated GFR ( eGFR ) of > 50 % ( if baseline < 60 ml/min/1.73 m(2 ) ) ; ( 2 ) reduction in eGFR of 30 ml/min/1.73 m(2 ) ( if baseline > or = 60 ml/min/1.73 m(2 ) ) ; ( 3 ) progression to ESRD ( need for dialysis , renal transplant , or eGFR < 15 ml/min/1.73 m(2 ) ) ; or ( 4 ) death . The secondary endpoint is time to change in eGFR or ESRD . Tertiary endpoints are cardiovascular events , slope of change in eGFR , and change in albuminuria at 1 yr . Specific safety endpoints are serious hyperkalemia ( potassium > 6 mEq/L , requiring admission , emergency room visit , or dialysis ) , all-cause mortality , and other serious adverse events . This paper discusses the design and key method ological issues that arose during the planning of the study The primary results of a three-year prospect i ve , double-blind , placebo-controlled trial in non-insulin-dependent diabetic ( NIDDM ) patients show that an anti-hypertensive regimen , which includes the ACE inhibitor enalapril , preserves renal function to a greater extent than therapy with antihypertensive agents excluding ACE inhibitors ( J Am Soc Nephrol 3:335 , 1992 ) . The influence of baseline urinary albumin excretion on the renal protective effects of enalapril treatment in these subjects was the objective of this further analysis . Adequate data were available in 121 patients of the 165 hypertensive NIDDM individuals studied [ baseline glomerular filtration rate ( GFR ) 30 to 100 ml/min/1.73 m2 ] . Twenty-four hour urinary excretion of albumin ( UAE ) , protein , urea nitrogen , creatinine and isotopically determined GFR were measured at baseline and six month intervals . Glycemic control and blood pressure regulation were assessed every three months . The rate of loss of GFR was significantly greater in patients with overt proteinuria at baseline ( UAE > 300 mg/24 hr ) as compared to patients with baseline sub- clinical proteinuria ( UAE < or = 300 mg/24 hr ) . Antihypertensive treatment with enalapril  preserved GFR significantly better ( P < 0.01 ) in the patients with sub- clinical proteinuria at baseline ( UAE < or = 300 mg/24 hr ) than other antihypertensive treatments which excluded the ACE inhibitor . Furthermore , only 7 % of the enalapril-treated group progressed to clinical albuminuria compared to 21 % of control treated patients . Although the enalapril-treated group had a lower mean blood pressure during the maintenance period , no correlation between blood pressure ( systolic , diastolic or mean arterial ) and rate of change of GFR was observed . ( ABSTRACT TRUNCATED AT 250 WORDS Renal interstitial expansion is now considered a useful marker of progression of several nephropathies . This study describes a multicenter , prospect i ve , double-blind , placebo-controlled , r and omized trial of the effects of Perindopril ( 4 mg/d ) on kidney structure and function over 2 yr in 26 type 2 diabetic patients with proteinuria ranging from 70 to 4210 mg/d and relatively preserved GFR ( creatinine clearance > 60 ml/min ) . All patients underwent baseline renal biopsy , but four ( 15 % ) were not r and omized because of the presence of nondiabetic nephropathy . The remaining 22 were r and omized ( 11 to  Perindopril  [ PE ] , 11 to placebo [ PO ] ) , and 19 ( 9 PE , 10 PO ) underwent follow-up biopsy  at 2 yr . BP was controlled equally in both groups throughout . Proteinuria increased in PO patients ( + 1562 mg/d ) but declined in PE patients ( -156 mg/d ) ( P < 0.05 ) . Morphometric analysis was performed by light microscopy using a Biocom computer . Over the 2 yr , mean cortical interstitial fractional volume identical at baseline increased significantly in PO patients ( 31.7 + /- 5.3 versus 40.2 + /- 11.1 % ; P = 0.001 ) but was unchanged in PE patients ( 33.8 + /- 4.9 versus 34.7 + /- 6.6 % ; P = 0.50 ) . It is concluded that : ( 1 ) nondiabetic nephropathy is present in approximately 15 % of albuminuric type 2 diabetic patients ; and ( 2 ) Perindopril prevents interstitial expansion in hypertensive patients with biopsy-proven diabetic glomerulopathy . These results support a role of angiotensin II in the progression of interstitial changes in type 2 diabetic patients with nephropathy Background —The aim of this study was to assess the level of urinary albumin excretion ( microalbuminuria ) , which is associated with increased risk of coronary heart disease and death , in the population . Microalbuminuria has been suggested as an atherosclerotic risk factor . However , the lower cutoff level of urinary albumin excretion is unknown . It is also unknown whether impaired renal function confounds the association . Methods and Results —In the Third Copenhagen City Heart Study in 1992 to 1994 , 2762 men and women 30 to 70 years of age underwent a detailed cardiovascular investigation program  , including a timed overnight urine sample . The participants were then followed up prospect ively by registers until 1999 with respect to coronary heart disease and until 2001 with respect to death . During follow-up , 109 incident cases of coronary heart disease and 276 deaths were traced . A urinary albumin excretion above the upper quartile , ie , 4.8 μg/min , was associated with increased risk of coronary heart disease ( RR , 2.0 ; 95 % CI , 1.4 to 3.0 ; P < 0.001 ) and death ( RR , 1.9 ; 95 % CI , 1.5 to 2.4 ; P < 0.001 ) independently of age , sex , renal creatinine clearance , diabetes mellitus , hypertension , and plasma lipids . Lower levels of urinary albumin excretion were not associated with increased risk . Conclusions —Microalbuminuria , defined as urinary albumin excretion > 4.8 μg/min ( corresponding to ≈6.4 μg/min during daytime ) , is a strong and independent determinant of coronary heart disease and death . Our suggestion is to redefine microalbuminuria accordingly and perform intervention studies 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 ) 
    Output:
    
There was a significant reduction in the risk of nonfatal cardiovascular events with ACEI versus placebo but not with ARB versus placebo , ACEI versus ARB or with combined therapy with ACEI + ARB versus monotherapy .
Development of end-stage kidney disease and progression of microalbuminuria to macroalbuminuria were reduced significantly with ACEI versus placebo and ARB versus placebo but not with combined therapy with ACEI + ARB versus monotherapy .
CONCLUSIONS ACEI and ARB exert independent renal and nonfatal cardiovascular benefits while their effects on mortality and fatal cardiovascular disease are uncertain .
There is a lack of evidence to support the use of combination therapy .