Chronic Kidney Disease and Hypertension

A Destructive Combination

Leticia Buffet, PharmD; Charlotte Ricchetti, PharmD, BCPS, CDE

Disclosures

US Pharmacist 

In This Article

Treatment

Agents that not only lower BP but also reduce proteinuria are recommended as first-line therapy for most patients with CKD and HTN; data indicate there may be significant long-term benefits in both cardiovascular and renal outcomes when proteinuria is decreased.[9] Several classes of antihypertensive agents may have a role in the treatment of CKD and HTN. Agents that target the renin-angiotensinaldosterone system (RAAS), such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), are generally considered first-line antihypertensive therapy for this patient population.[8,9,18] Table 2 provides guidance on recommended antihypertensive agents for patients with CKD with or without diabetes and with or without proteinuria.

ACE Inhibitors or ARBs

Studies have shown that antihypertensive agents that target the renin-angiotensin system prevent kidney decline more so than other agents, even when achieving similar BP goals.[19] These results were found primarily in patients with proteinuria, whereas the benefit was less substantial for those without proteinuria. Based on these findings, guidelines recommend ACE inhibitor or ARB therapy as first-line treatment for those with diabetes or those presenting with nondiabetic kidney disease, HTN, and proteinuria. Data indicate that ACE inhibitors and ARBs are equally effective in lowering BP and reducing proteinuria.[20] A recent meta-analysis suggests that ACE inhibitor therapy may provide superior benefit over ARB therapy for the treatment of HTN due to a 10% reduction in all-cause mortality.[21] These results were determined for patients with HTN and did not apply to patients with additional comorbidities such as CKD. Therefore, selection of one agent over another will depend on patient-specific factors such as potential for side effects and cost. Treatment with both an ACE inhibitor and an ARB is not recommended, as this combination has been shown to worsen kidney function. Combination ACE inhibitor and ARB therapy did not reduce cardiovascular mortality or morbidity in comparison to monotherapy of an ACE inhibitor.[20,21]

ACE inhibitors and ARBs are generally well tolerated. ACE inhibitors may cause a dry cough, which unfortunately often requires a change in therapy. ARBs are not associated with dry cough. Angioedema is very rare; however, patients started on ACE inhibitors or ARBs should be informed of the signs and symptoms that may present with angioedema. Inform patients that angioedema is unlikely, but if they experience swelling in their face (often including the eyelids) and/or extremities, they should discontinue treatment and seek medical attention immediately.[18]

Thiazide vs. Loop Diuretics

For patients without proteinuria, a preferred first-line therapy has not been clearly established, and other agents, such as a thiazide, may be considered. Patients with CKD and HTN often experience fluid retention or fluid overload. As a result, diuretics are often necessary in their treatment regimen. Thiazides are recommended for patients with CKD stages 1 to 3 (GFR ≥30 mL/min), and have been established as effective agents for BP and CVD risk reduction.[22] Loop diuretics are recommended for patients with CKD stage 4 or 5 (GFR <30 mL/min), as they have been shown to be more effective in reducing extracellular fluid volume in patients with severely reduced GFR.[18] However, the long-term effect of loop diuretics on cardiovascular outcomes has not been clearly established.[23]

Thiazide diuretics (chlorthalidone, hydrochlorothiazide) and loop diuretics (bumetanide, furosemide, torsemide) all cause hyperuricemia (increased urination). This increase in fluid loss may lead to electrolyte imbalance. It is important for patients on these agents to have their electrolytes monitored to ensure they do not experience electrolyte abnormalities such as hyperkalemia or hypomagnesemia. Orthostatic hypotension may occur in response to any antihypertensive agents; however, it is common with diuretics. It is important to counsel patients initiating diuretic therapy on the need to rise slowly from a sitting or lying-down position.[24,25]

Calcium Channel Blockers

Calcium channel blockers (CCBs) are considered second- or third-line therapy in the treatment of HTN in patients with CKD.[8,9] While there may be no difference in the effect on BP lowering between nondihydropyridine CCBs (ND-CCBs; e.g., diltiazem, verapamil) and dihydropyridine CCBs (e.g., amlodipine, nifedipine), ND-CCBs have been shown to significantly reduce proteinuria either when used alone or in combination with an ACE inhibitor or an ARB.[26] Because of their potential to reduce proteinuria, in addition to their antihypertensive effects, ND-CCBs should be considered as second- or third-line therapy in patients with diabetic CKD or nondiabetic CKD with proteinuria. Dihydropyridine CCBs can be used as second-line agents in patients with nondiabetic CKD without proteinuria. Common adverse effects include edema and constipation with ND-CCBs (especially verapamil) and flushing and peripheral edema with dihydropyridine agents.[18]

Aldosterone Antagonists

Aldosterone plays a severely deleterious role in the progression of CKD. Aldosterone receptor antagonists (e.g., spironolactone, eplerenone) may have a place in the role of CKD therapy when BP goals have not been achieved with first- and second-line therapy. These agents have shown in human trials to provide a reduction in proteinuria when added to an ACE inhibitor or ARB.[27,28]

Aldosterone antagonists are potassium-sparing diuretics, which increase the risk for hyperkalemia, particularly if taken with an ACE-inhibitor or ARB. It is important for patients initiated on potassium-sparing diuretics to have their potassium levels checked to ensure they do not experience electrolyte abnormalities. Symptoms of hyperkalemia include heart arrhythmia and severe muscle weakness. Unfortunately, hyperkalemia may present asymptomatically, which underscores the importance of monitoring.[18,27]

Renin Inhibitor

Aliskiren is the only renin inhibitor currently available on the market. It is indicated for the treatment of HTN as monotherapy or as combination therapy with valsartan. Recent data from the ALTITUDE trial have lead to the contraindication of its use with ACE inhibitors or ARBs in patients with diabetes or renal impairment (GFR <60 mL/min) due to the increased risk for renal impairment, hypotension, and hyperkalemia.[29] Aliskiren can be considered if the patient cannot take an ACE inhibitor or an ARB; however, its use cannot be recommended in patients with stage 4 or 5 renal failure.[30]

Beta-blockers

Data that evaluate the effect of beta-blockers on the progression of CKD and proteinuria are limited.[27] While beta-blockers are not included in Table 2, these agents can be considered as second- or third-line therapy if the patient has a compelling indication for a beta-blocker such as coronary artery disease or chronic heart failure.[18]

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