Brenner, B. M. et al. RENAAL Study. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861-869

University of Groningen, Groningen, Groningen, Netherlands
New England Journal of Medicine (Impact Factor: 55.87). 09/2001; 345(12):861-9. DOI: 10.1056/NEJMoa011161
Source: PubMed


Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy.
A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease.
A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo).
Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.

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Available from: Shahnaz Shahinfar, Aug 05, 2014
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    • "Likewise, trials in type 1 [94] [110] and type 2 diabetes [111] [112] documented that whenever proteinuria is decreased by treatments, progression to end-stage renal disease is reduced. As already mentioned, the Reduction of Endpoints in type 2 diabe‐ tes with the Angiotensin II Antagonist Losartan (RENAAL) study [111] in 1513 patients with type 2 diabetic nephropathy confirmed that more reduction in proteinuria by losartan invar‐ iably was associated with more renoprotection at comparable levels of blood pressure con‐ trol. Beneficial cardiovascular effects of losartan also were driven by effects on urinary protein and largely depended on the amount of residual proteinuria. "
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    • "Furthermore, ARBs have recently attracted attention for their direct anti-fibrotic activity. In particular, ARBs may have the potential to inhibit fibrotic change in chronic kidney disease by reducing TGF-β1 expression [33] [34] [35]. "
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    • "At 3.4 years, losartan reduced the same composite end point by 16%. Losartan reduced the incidence of serum creatinine doubling by 25% and the risk of ESRD by 28% [81]. Both studies showed that the benefit of ARBs exceeded that attributable to changes in BP alone. "
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    ABSTRACT: Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with diabetes. This complication reflects a complex pathophysiology, whereby various genetic and environmental factors determine susceptibility and progression to end-stage renal disease. DN should be considered in patients with type 1 diabetes for at least 10 years who have microalbuminuria and diabetic retinopathy, as well as in patients with type 1 or type 2 diabetes with macroalbuminuria in whom other causes for proteinuria are absent. DN may also present as a falling estimated glomerular filtration rate with albuminuria as a minor presenting feature, especially in patients taking renin–angiotensin–aldosterone system inhibitors (RAASi). The pathological characteristic features of disease are three major lesions: diffuse mesangial expansion, diffuse thickened glomerular basement membrane, and hyalinosis of arterioles. Functionally, however, the pathophysiology is reflected in dysfunction of the mesangium, the glomerular capillary wall, the tubulointerstitium, and the vasculature. For all diabetic patients, a comprehensive approach to management including glycemic and hypertensive control with RAASi combined with lipid control, dietary salt restriction, lowering of protein intake, increased physical activity, weight reduction, and smoking cessation can reduce the rate of progression of nephropathy and minimize the risk for cardiovascular events. This review focuses on the latest published data dealing with the mechanisms, diagnosis, and current treatment of DN.
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