Dr Rutecki is with the Cleveland Clinic National Consultation Service.
Quiz: The use of ACEIs and ARBs to treat hypertension in moderate-to-severe kidney disease is a murky area of medicine. Test what you know, here.
In a recent article on collaboration among specialties in treating patients with hypertension complicated by a variety of comorbidities, we explored medication choices available in the settings of chronic kidney disease (CKD), diabetes, and heart disease.1 In that series of short quizzes on the selection of antihypertensive medication, the emphasis was on the benefits a specific blood pressure agent might extend to a comorbidity (ACEI or ARBs in patients with heart failure, diabetes, and proteinuria, for example) as well as the potential adverse effect the antihypertensive might have on a specific comorbid disease (eg, metoprolol can increase insulin resistance in diabetics with hypertension and ACEIs/ARBs can worsen renal function or cause hyperkalemia).
Let’s narrow the focus here to hypertension and CKD alone and test your knowledge of the current science and clinical medicine.
Strict blood pressure control in the Modification of Diet in Renal Disease (MDRD) and African American Study of Kidney Disease and Hypertension (AASK) trials decreased the risk of death in the CKD population.2 In the NHANES II Study, a GFR <70 cc/min was associated with a higher adjusted risk of cardiovascular death.3 A prominent cardiovascular risk factor in the CKD population is hypertension. Three multiple choice questions will feature 3 important subtopics within the CKD-hypertension spectrum.
Should we stop ACEIs/ARBs in CKD stages 4 and 5?
ACEIs and ARBs are frequently prescribed for patients with hypertension and CKD, especially those with accompanying diabetes, proteinuria and/or heart failure. That said, did you know that there are no studies demonstrating the benefits of ACEI or ARB therapy in reducing cardiovascular events in persons with advanced CKD not on dialysis?4 Furthermore administration of ACEI-ARBS can interfere with renal autoregulation leading to a further decline in GFR.4 Discontinuation of ACEI/ARBs in advanced CKD may prevent episodes of acute renal failure that can lead to earlier dialysis initiation.4
1. Which is the best single answer from the choices below for the question: Should ACEI/ARBS be stopped in advanced CKD?
A. One study demonstrated a nephroprotective effect from ACEIs/ARBs across minimal to severe proteinuria in persons with CKD.
B. If ACEI/ARB therapy in the CKD demographic is beneficial, using both classes will likely confer additional protections.
C. It is unclear presently as to whether ACEI/ARBS have positive or negative effects in advanced CKD.
D. There are currently no studies underway to address this important question.
The correct answer is: C. It is unclear presently as to whether ACEI/ARBS have positive or negative effects in advanced CKD.
Post hoc analysis of the REIN-2 Study in non-diabetic patients proved that ACEI/ARBS did not confer renal protective effects if the proteinuria was <1.5 grams/day.4 Results from several studies (ONTARGET, ALTITUDE VA NEPHRON D) have cautioned that dual blockade (both an ACEI and an ARB) is unsafe.4 It is true that there are no studies at present to answer the question of the safety of ACEIs/ARBs in advanced CKD, but the STOP ACEI Trial already underway will determine whether stopping ACEIs will stabilize renal function in a cohort with advanced CKD.4
What to do about ACEI side effects like angioedema
I am asked frequently whether it is safe to switch from an ACEI to an ARB in patients who experience angioedema as a complication of an ACEI.
2. Of the options below, which one answers that question best?
A. Patients who experience angioedema on an ACEI can be trialed on another ACEI because angioedema is not a class effect of this group of medications.
B. ACEI angioedema always develops early after medication initiation.
C. If an ARB is started soon after the event of angioedema and the angioedema recurs, it may be assumed that the ARB is responsible.
D. Patients who developed ACEI angioedema can experience relapses (even if ACEIs are completely eliminated) from the original ACEI up to 6 months later.
The correct answer is: D. Patients who developed ACEI angioedema can experience relapses (even if ACEIs are completely eliminated) from the original ACEI up to 6 months later.
Angioedema while on ACEIs is a class effect and other ACEIs will cause the same problem.5 Although some individuals can develop angioedema one day after initiation of therapy, others experience this side effect 8-10 years later.5 When blaming other medications for angioedema after an ACEI is discontinued, remember that the original ACEI can be associated with angioedema relapses for as long as 6 months! If these are ascribed to an ARB, they may remove an important medication from the patient’s regimen.
Are diuretics appropriate only for patients with reasonable GFRs?
Is there a place for furosemide or other potent diuretics in patients with advanced CKD (even on dialysis) who have hypertension or heart failure? I have entertained the notion that someone with a rock bottom GFR, especially if they are already on dialysis for fluid removal, would garner no additional benefit from a diuretic.
3. Which of the following statements is/are accurate? (You may choose more than one)
A. Loop diuretics do not increase urine volumes in oliguric CKD patients
B. Ototoxicity is common in CKD patients given higher oral doses of loop diuretics.
C. Increased urine output in hemodialysis patients is associated with lower mortality.
D. Loop diuretics in dialysis patients preserve residual renal function.
The correct options are: C. Increased urine output in hemodialysis patients is associated with lower mortality; and D. Loop diuretics in dialysis patients preserve residual renal function.
Studies have shown that loop diuretics can increase urine volume in patients making as little as 100 cc/urine a day.6 The risk of ototoxicity with oral compared to intravenous loop diuretics in CKD patients is very small.6 Increased urine output and residual renal function are both associated with benefits in dialysis patients.6
I have changed my attitudes regarding medications and blood pressure management in CKD considerably. I now question the benefit of carte blanche ACEI/ARBS in CKD and I am in eager anticipation of the publication of the STOP ACEI study results. I will not be quick to blame an ARB for angioedema after an ACEI is discontinued. I will not swear off diuretics in individuals with decreased GFRs. Although the loop diuretic may not be helping with blood pressure control, increased urine output in this demographic is a good thing.