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RAS Inhibitors Integral to Treatment of Chronic Kidney Disease


Modify RAS Activity as Part of Your BP-Lowering Strategy

By Wayne Kuznar

CHICAGO—Inhibition of the renin-angiotensin system (RAS) as part of a blood pressure (BP)-lowering strategy reduces the risk of cardiovascular and renal events, regardless of the level of kidney function, in patients with chronic kidney disease (CKD), said Matthew Weir, MD, at the American Society of Hypertension annual meeting.

An increase in serum creatinine levels with the use of RAS inhibitors can be expected in patients with impaired kidney function. Because of this increase in creatinine, many physicians are reluctant to use these agents in patients with elevated serum creatinine levels or a reduced estimated glomerular filtration rate (eGFR).

Inhibitors of the RAS facilitate dilatation of the efferent arteriole of the glomerulus, thereby lowering glomerular capillary pressure. "Because they are designed to reduce glomerular capillary pressure, there will be a functional increase in serum creatinine [with a RAS inhibitor], or a decrease in eGFR, which on average can be anywhere from 15% to 30%, depending on the volume status of the patient, the renal artery anatomy, and other cotherapies," said Dr Weir, director, Division of Nephrology, University of Maryland, Baltimore. "So, this is a functional change in GFR that results in a long-term anatomical advantage."

RAS blockers are also more effective than other classes of antihypertensives at reducing central aortic pressures, which may contribute to their beneficial effect on the kidney.

CKD is a burgeoning problem that would be even more severe if these patients were not dying first of heart disease or stroke, said Dr Weir. "The kidney and the heart are closely tied together," he said. "It's fair to say that most classic Framingham risk factors explain much of the relationship between the two."

The Cardiovascular Health Study found that once GFR starts to fall, the likelihood of cardiovascular events starts to increase, especially as eGFR drops to <60 mL/min/1.73 m2.

"People with chronic kidney disease benefit as much as people without chronic kidney disease from appropriate medications and therapy, if not more, because of their increased risk," said Dr Weir. "These are people who need global cardiovascular risk-reduction measures, because decreased GFR has consistently been found to be an independent risk factor for cardiovascular outcomes and all-cause mortality."

These risk-reduction measures include treating to BP goals, treating lipids, dietary modifications, antiplatelet therapies, managing anemia and calcium phosphorus, and possibly extinguishing microalbuminuria or proteinuria.

Although a BP of <130/80 mm Hg is a stated goal for patients with CKD, some patients may benefit from even more aggressive antihypertensive therapy.

Modifying the activity of the RAS should be a part of the BP-lowering strategy, said Dr Weir, especially in the presence of higher serum creatinine levels. In the Heart Outcomes Prevention Evaluation study, participants who had serum creatinine levels >1.4 mg/dL had a substantial reduction in vascular risk if randomized to the angiotensin-converting-enzyme (ACE) inhibitor ramipril (Altace) compared with placebo; this reduction in risk was not as dramatic in the patients with creatinine levels <1.4 mg/dL.

The Collaborative Diabetic Nephropathy study supports a greater reduction in risk with ACE inhibition as serum creatinine levels increase. This study also showed a greater advantage to ACE inhibition in patients with substantial proteinuria. "The sicker the kidney, the greater advantage of the ACE inhibitors," said Dr Weir.

A fear of inducing hyperkalemia is often cited for not using RAS-blocking agents in patients with higher creatinine levels or a loss of substantial kidney function, but recent data show no dramatic difference in study drug discontinuation due to hyperkalemia in such patients randomized to ACE inhibitors or angiotensin receptor blockers compared with placebo, he said.

"Alterations in serum creatinine and potassium are predictable, and RAS blocker discontinuation is almost always avoidable," said Dr Weir.

If creatinine level increases >30% with the use of a RAS-blocking agent in a patient with CKD, he recommends evaluating the patient's diuretic use and volume status and ruling out concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs). If neither is the culprit, rule out clinically significant renal disease.

If serum potassium increases >0.5 mmol/L with use of a RAS blocker, rule out excessive consumption of fruit or other high potassium-content foods, concomitant NSAID use, or the use of salt substitutes. Also rule out type IV renal tubular acidosis and the use of potassium-sparing diuretics.

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