Dual renin-angiotensin system blockade for nephroprotection.

In experimental diabetic and nondiabetic chronic kidney disease, angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blockers (ARB) combination therapy reduce proteinuria and prevent structural lesions more effectively than either drug alone. Consistently, in humans, a multidrug individually tailored antiproteinuric treatment based on combination therapy with maximum tolerated doses of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers ("Remission Clinic") reduced proteinuria and prevented end-stage renal disease more effectively than angiotensin-converting enzyme/angiotensin receptor blockers monotherapy, in particular in subjects with nondiabetic chronic kidney disease. Fixed doses of an angiotensin-converting enzyme inhibitor or renin inhibitor added-on losartan failed to exert any additional renoprotective effect as compared with losartan monotherapy in patients with type 2 diabetes and overt nephropathy. However, the VA NEPHRON D study found that losartan and lisinopril combination therapy reduced by 34 % the risk of pre-defined reductions in estimated glomerular filtration rate, end-stage renal disease or death as compared to losartan in 1448 type 2 diabetes patients with overt nephropathy. Unfortunately, treatment effect failed to achieve the nominal significance (P=0.07) because of premature trial interruption. Thus, the Remission Clinic protocol is the most powerful tool to prevent progression to end-stage renal disease in nondiabetic proteinuric chronic kidney disease. Results of the ongoing VALID trial will show whether this approach can be safely extended to type 2 diabetes patients.