Dual Renin-Angiotensin System Blockade for Nephroprotection: Still under Scrutiny

In experimental diabetic and non-diabetic chronic kidney disease (CKD), angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) combination therapy reduces proteinuria and prevents 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 ACEi and ARB (Remission Clinic protocol) reduced proteinuria and prevented end-stage renal disease (ESRD) more effectively than ACEi/ARB monotherapy, in particular in subjects with non-diabetic CKD. Fixed doses of an ACEi or renin inhibitor added to losartan failed to exert any additional renoprotective effect as compared with losartan monotherapy in patients at increased cardiovascular risk (ONTARGET study) or with type 2 diabetes and overt nephropathy (ALTITUDE study). The VA NEPHRON D study found that losartan and lisinopril combination therapy reduced by 34% the risk of predefined reductions in estimated glomerular filtration rate, ESRD or death as compared to losartan in 1,448 type 2 diabetes patients with overt nephropathy. Unfortunately, the 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 ESRD in non-diabetic proteinuric CKD. Results of the ongoing VALID trial will show whether this approach can be safely extended to type 2 diabetes patients.