The sixth report of the Joint National Committee (JNC VI) has recommended that angiotensin-converting enzyme (ACE) inhibitors be used for lowering blood pressure in patients with diabetes mellitus and in persons with renal insufficiency. Blood pressure reduction is known to slow renal disease regardless of the antihypertensive agent used, but ACE inhibitors may further slow renal disease progression in patients with diabetic nephropathy. However, only one half of the 53 percent of hypertensive patients treated actually achieve blood pressure reduction to less than 140/90 mm Hg. Some patients may experience a transient rise in serum creatinine level after starting treatment with an ACE inhibitor or an angiotensin receptor blocker (ARB), or after blood pressure is adequately controlled. A rise in serum creatinine or potassium level may result in discontinuation of the drug or use of lower dosages than what is recommended because of concerns about safety and tolerability in patients with renal insufficiency. Bakris and Weir reviewed 12 randomized trials to determine if an initial reduction in the glomerular filtration rate (GFR) or elevation of serum creatinine levels from use of ACE inhibitors or ARBs results in long-term protection against decline in renal function in patients with renal insufficiency.

Renal disease progression among patients with preexisting renal insufficiency was evaluated over a three-year period. The evaluations included patients with and without diabetes mellitus or systolic heart failure. GFR data was used if serum creatinine values were unavailable.

A limited elevation in serum creatinine level (30 percent or less above baseline) was seen following initiation of therapy with an ACE inhibitor or ARB in patients who achieved their blood pressure goal. The increase usually occurred within two weeks of therapy. Regardless of the serum creatinine value, manifestations of renal failure were not apparent until the GFR was well below 30 mL per minute. Patients with the greatest degree of renal insufficiency experienced the greatest protection from renal disease progression. As renal disease increases, there is a loss of renal reserve as well as the autoregulatory ability of the kidney, resulting in a more acute fall in GFR following ACE inhibition. The studies also indicated that there is a low risk (less than 2 percent) of hyperkalemia with use of drugs that block the reninangiotensin system (RAS).

Results indicated that use of drugs that block the RAS is appropriate in patients with renal insufficiency. Once marked elevations in serum creatinine levels are present and renal reserve is lost, the unique benefits of ACE inhibitors may not exceed that of achieving the recommended level of blood pressure reduction alone. Data from these studies in patients with diabetic and nondiabetic renal disease demonstrated that if an elevation in the serum creatinine level does occur, it stabilizes quickly and does not progressively worsen. In addition, this reduction in GFR is reversible. The authors conclude that no one should be denied a long-term trial of an ACE inhibitor because of a preexisting elevation of serum creatinine level or one that increases up to 30 percent from baseline and then stabilizes within two to three weeks. If elevations in serum creatinine of more than 30 percent occur on a chronic basis within the first month or if hyperkalemia occurs, the drug should be withdrawn (see the accompanying figure on page 1152).