Supranormal excretion of albumin in the urine portends decline in renal function. Although transient increases in urine protein may be seen in otherwise healthy individuals with fever or vigorous physical exercise, sustained elevations of albumin are a marker for chronic kidney disease (CKD). To date, numerous clinical trials have shown that treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) can have favorable effects on urinary protein excretion, whether the patient has underlying hypertension. There has been controversy over whether combined ACE inhibitors + ARBs might be more beneficial than either agent alone. A recent large clinical trial (ONTARGET) — although not powered to determine renal outcomes — found a concerning increase in endstage renal disease in study subjects treated with ACE inhibitors + ARBs.

The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) study enrolled CKD patients with proteinuria, all of whom were treated with losartan (ARB), and half of whom were randomized to the addition of lisinopril. The primary endpoint of the study was change in glomerular filtration rate.

The study was discontinued prematurely by recommendation of the data and safety monitoring committee based on the burden of serious adverse events (e.g., hyperkalemia, acute kidney injury) combined with the low likelihood of a favorable effect on the primary endpoint. The prevailing opinion that ACE inhibitors + ARBs are not a favorable choice for addressing proteinuria is now further substantiated.

Source: Fried LF, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369:1892-1903.