ACE Inhibitors and ARBs: Antihypertensive Medications in CKD
Charlotte Szromba
K/DOQI Clinical Practice Guidelines
The publication of the new K/DOQI clinical practice guidelines on
hypertension and antihypertensives agents in CKD provide a foundation
for selection of medications for patients with specific causes of
kidney disease. Although any type of antihypertensive medication can be
used to lower blood pressure in the patient with CKD, some benefit will
be obtained by using specific classes of agents in certain clinical
situations. The goals of antihypertensive therapy are to lower blood
pressure, reduce the risk of cardiovascular disease, and slow
progression of CKD. The accepted target blood pressure goal to reduce
cardiovascular disease should be less than 130/80 mmHg (National Kidney
Foundation [NKF], 2004).
Renal effects of ACE inhibitors and ARBs
Renin is normally released from the juxtaglomerular cells in response
to stimuli such as decreased blood flow to the kidney or increased
sympathetic tone. The substrate angiotensininogen is then formed into
angiotensin I, which is converted to angiotensin II via the activity of
several enzymes, including angiotensin converting enzyme (ACE) and
chymase. Angiotensin II has two target receptors, AT1 and AT2.
The A1 receptors can cause efferent arteriole constriction, which
increases intraglomerular pressure. A2 receptors produce antagonistic
effects on efferent arterioles (NKF, 2004). These processes can lead to
endothelial injury, increased glomerular wall tension and increased
glomerular permeability to macromolecules such as protein. The protein
is concentrated in the proximal tubules causing excessive tubular
protein reabsorption, which results in glomerular scarring. Medications
that block the renin-angiotensin-aldosterone system (RAS) such as ACE
inhibitors or an angiotensin receptor blocker (ARB) are the primary
basis of therapy because they disrupt processes that cause additional
injury to the kidney, decrease protein excretion, and are considered
renalprotective (McCullough, 2004).
In the African-American Study of Kidney Disease and Hypertension
(AASK), individuals were randomized to treatment with an ACE inhibitor,
a beta-blocker or a dihydropyridine calcium channel blocker. Although
no difference was observed in the groups for the primary outcome of
rate of change of GFR, the ACE inhibitor group was more effective in
decreasing the secondary composite outcome (50% reduction of GFR, ESRD
or death). A larger beneficial effect was noted in patients with higher
levels of proteinuria (NKF, 2004). Therapy in Diabetic Kidney Disease
ACE inhibitors and ARBs have shown to be effective in slowing the
progression of kidney disease in patients with microalbuminuria (20-200
ug/min) due to either type 1 or 2 diabetes because they decrease
albumin excretion, slow the increase in albumin excretion and delay
progression to macroalbuminuria (>200 ug/min). A review of several
studies conducted over the years using ACE inhibitors in type 1
diabetes demonstrates the effectiveness of these agents in reducing
albuminuria and slowing the decline of renal function (NKF, 2004).
Findings from the Irbesartan Diabetic Nephropathy Trial (IDNT) and the
Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan
(RENAAL) indicate that ARBs are more effective than other agents in
slowing the progression of kidney disease in patients with
macroalbuminuria due to type 2 diabetes. ACE inhibitors and ARBs are
also the agents of choice in nondiabetic kidney disease with
proteinuria (NKF, 2004).
Combining ACE Inhibitors and ARBs
Recent
clinical trials have indicated that angiotensin II can be generated by
enzymes other than ACE and that angiotensin II and other RAS peptides
bind to receptors with differing functional consequences. The RAS
system is more complex than previously thought. So it appears that
neither ACE inhibitors nor ARBs can completely block the RAS system
(Wolf & Ritz, 2005). Several small scale clinical studies in the
past few years have indicated that combination therapy with both ACE
inhibitors and ARBs are more potent in reducing proteinuria and
decreasing blood pressure (Wolf & Ritz, 2005).
The COOPERATE Trial involved 263 Japanese patients with nondiabetic
kidney disease who were assigned randomly to an ACE Inhibitor, an ARB,
or a combination. The findings indicate that the largest decrease in
proteinuria was seen in the combination group and that doubling of
serum creatinine or ESRD was less common with the combination therapy
(Rose & Bakris, 2005). The data are limited, side effects can
decrease effectiveness, and these agents in combination have not been
tested in all types of CKD, so they should be reserved for high risk
patients (NKF, 2004).
Adverse Effects of ACE Inhibitors and ARBs
The
incidence of adverse effects from ACE inhibitors and ARBs ranges from
5% to 20%. Effects due to interfering with RAS system such as
hypotension and hyperkalemia are usually dose related and can be
ameliorated by slow dose titration and decreasing doses or
discontinuation. (NKF, 2004).
In patients with CKD, there is an impairment of renal autoregulation,
so any decrease in intraglomerular pressure due to a decrease in
systemic blood pressure will cause a vasodilatation of the efferent
side of the glomerulus, leading to a decline in the glomerular
filtration rate and an increase in serum creatinine levels (Palmer,
2002). The GFR should be monitored frequently, especially after
initiation or titration of doses. The ACE Inhibitor or ARB can be
continued if the decline in GFR over 4 months is less than 30% from
baseline value (NKF, 2004).
Hyperkalemia is defined by K/DOQI guidelines as an elevation of serum
potassium concentration to greater than 5.0mEq/L and can occur more
frequently with ACE inhibitors than with ARBs. Dietary reduction of
potassium intake, use of loop diuretics, correction of metabolic
acidosis, and use of sodium polystyrene sulfonate (Kayexalate) can be
used to treat hyperkalemia. The ACE inhibitor or ARB can be continued
if the serum potassium level is less than 5.5 mEq/L (NKF, 2004).
Angioneurotic edema is relatively rare, (less than 1%) and occurs more
frequently in African Americans than Caucasians. Patients should be
counseled about this reaction and should contact their health care
professional immediately or proceed to the emergency room (NKF, 2004).
Cough is related to the effect of ACE inhibition on other enzymes and
an ARB can be prescribed as an alternate therapy.
ACE inhibitors should be used with caution in patients with suspected
renal artery stenosis, decreased intravascular volume, sepsis, and
concurrent use of NSAIDs because these conditions can cause acute renal
failure (Palmer, 2002).
All women of child- bearing age should be counseled about the adverse
effects of ACE inhibitors and ARBs on the fetus. If pregnancy occurs
while taking these medications they should be discontinued as soon as
possible (NKF, 2004).
Educating and Encouraging Self-Management Behaviors
Success
in management of hypertension in CKD is not achieved by medication
alone. Certain lifestyle changes such as diet adjustment, smoking
cessation, exercise, decrease in alcohol consumption and
self-monitoring of blood pressure are important components of the
treatment plan. Typical information from patient education
indicates that only 30% to 39% of patients with hypertension achieve
adequate blood pressure control (NKF, 2004). Newer approaches stress
problem solving, goal setting, and social support while validating the
central role played by the patients in managing their illness. Other
self-management principles are related to enhancing the patient’s
ability to gain control over factors that influence their behavior and
looking at barriers to adherence. Side effects are related to the class
of medication prescribed and recent studies indicate that ARBs have the
highest adherence rate followed by ACE inhibitors. Once-a-day dosing or
combination medications can also be helpful in promoting adherence
(NKF, 2004).
References
McCullough,
P.A. (2004). Cardiovascular risk reduction and preservation of renal
function in the early nephropathy patient. Advances in Chronic Kidney
Disease 11(2), 184-191.
National Kidney Foundation. (2004). NKF-K/DOQI clinical practice
guidelines on hypertension and antihypertensive agents in chronic
kidney disease. American Journal of Kidney Disease 43(5) Supplement
1-268.
Palmer, B. (2002). Renal dysfunction complicating the treatment of
hypertension. New England Journal of Medicine 347(16) 1256-1261.
Rose, B.D., & Bakris, G.L. (2005). Antihypertensive therapy and
progression of renal failure. Retrieved March 7, 2005 from
www.uptodateonline.com
Wolf, G., & Ritz E. (2004). Combination therapy with ACE inhibitors
and angiotensin II receptor blockers to halt progression of chronic
renal disease: Pathophysiology and indications. Kidney International
67, 799-812.
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Clinical Consult department is designed to provide answers to questions
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