What is the best initial antihypertensive medication to add for a 65‑year‑old African American man with stage 3 chronic kidney disease (estimated glomerular filtration rate ≈45 mL/min/1.73 m²) who is already taking amlodipine 10 mg daily and spironolactone 100 mg daily?

Add an ACE Inhibitor or ARB as the Next Antihypertensive Agent

For this 65-year-old African-American patient with stage 3b CKD (eGFR 45 mL/min/1.73 m²) already on amlodipine and spironolactone, you should add an ACE inhibitor (such as lisinopril 10–20 mg daily) or an ARB (such as losartan 50–100 mg daily) as the next medication. This recommendation assumes the patient has albuminuria ≥30 mg/day; if albuminuria status is unknown, check a urine albumin-to-creatinine ratio immediately to guide therapy. 1, 2

Rationale for ACE Inhibitor or ARB

• ACE inhibitors or ARBs are first-line therapy for CKD patients with albuminuria ≥30 mg/day, providing both renal protection (slowing GFR decline) and cardiovascular benefit independent of blood pressure lowering. 1, 3

• In African-American patients with hypertensive CKD, the AASK trial demonstrated that ramipril (an ACE inhibitor) reduced the risk of doubling serum creatinine or progression to end-stage renal disease by 38% compared to amlodipine, even though this patient is already on amlodipine. The benefit was most pronounced in patients with proteinuria >0.22 g/g (approximately 220 mg/g). 2, 3

• The patient is already on a calcium-channel blocker (amlodipine 10 mg) and a mineralocorticoid receptor antagonist (spironolactone 100 mg), so the missing component of optimal CKD hypertension management is renin-angiotensin system (RAS) blockade. 1, 2

• Most CKD patients require three or more antihypertensive agents to achieve the target blood pressure of <130/80 mmHg, so adding a third mechanistically complementary agent is expected and appropriate. 1, 2

Blood Pressure Target

• Aim for <130/80 mmHg using standardized office measurement if the patient has albuminuria ≥30 mg/day. 1, 2

• If albuminuria is absent or <30 mg/day, a target of <140/90 mmHg is acceptable, as lower targets have not shown additional benefit in non-albuminuric CKD. 1

Critical Monitoring After Initiating ACE Inhibitor or ARB

• Check a basic metabolic panel (serum creatinine, potassium, eGFR) 2–4 weeks after starting or up-titrating the ACE inhibitor or ARB. 1, 2

• Continue the ACE inhibitor/ARB unless serum creatinine rises >30% within 4 weeks; a rise up to 30% reflects the intended hemodynamic effect and is acceptable. 1

• Monitor closely for hyperkalemia, especially given the patient is already on spironolactone 100 mg daily. If potassium rises above 5.5 mEq/L, consider reducing or discontinuing spironolactone rather than the ACE inhibitor/ARB, as the renoprotective benefit of RAS blockade is paramount. 1, 4, 5

• Hyperkalemia risk is elevated in this patient due to the combination of stage 3b CKD (eGFR 45), spironolactone use, and the planned addition of an ACE inhibitor/ARB. Studies show that 50% of CKD patients on spironolactone develop potassium ≥5.0 mEq/L within 4 weeks, though serious hyperkalemia (≥5.5 mEq/L) occurs in only 3–4% by 8 weeks. 4

Addressing the Spironolactone Regimen

• Spironolactone 100 mg daily is a high dose for a patient with eGFR 45 mL/min/1.73 m², and recent evidence questions its safety and efficacy in stage 3b CKD without heart failure or another explicit indication. 6

• The 2024 SPIRO-CKD trial (published in Nature Medicine) found that spironolactone 25 mg daily in stage 3b CKD patients (mean age 75 years) provided no cardiovascular benefit and was frequently discontinued due to safety concerns—35% stopped due to eGFR decline meeting prespecified criteria, 19% due to side effects, and 8% due to hyperkalemia. 6

• Consider reducing spironolactone to 25 mg daily or discontinuing it entirely unless the patient has resistant hypertension (uncontrolled on three agents including a diuretic) or heart failure with reduced ejection fraction, where spironolactone has proven mortality benefit. 6, 5

• If spironolactone is continued, strict monitoring of potassium and eGFR over the first month after adding an ACE inhibitor/ARB is mandatory, with standard surveillance thereafter. 4, 5

Medication Selection: ACE Inhibitor vs. ARB

• Either an ACE inhibitor or an ARB is appropriate; ACE inhibitors are typically first-line, but ARBs are a reasonable alternative if the patient develops ACE inhibitor-related cough. 1, 2

• Start lisinopril 10 mg daily or losartan 50 mg daily, and titrate to the maximum tolerated dose (lisinopril 40 mg or losartan 100 mg) over 4–8 weeks to achieve the blood pressure target and maximize renoprotective benefit. 1

• Never combine an ACE inhibitor with an ARB (dual RAS blockade), as this increases the risk of hyperkalemia, hypotension, and acute kidney injury without added benefit. 1

Albuminuria Assessment

• If the patient's albuminuria status is unknown, obtain a spot urine albumin-to-creatinine ratio immediately. The strength of the recommendation for ACE inhibitor/ARB therapy depends on the presence and degree of albuminuria. 1, 2

• If albuminuria is ≥300 mg/g, ACE inhibitor/ARB therapy is a strong (Class I) recommendation. 1

• If albuminuria is 30–300 mg/g, ACE inhibitor/ARB therapy is suggested (Class IIa). 1

• If albuminuria is <30 mg/g, a dihydropyridine calcium-channel blocker or thiazide diuretic is equally reasonable as first-line therapy, but since the patient is already on amlodipine, adding an ACE inhibitor/ARB remains appropriate to achieve the blood pressure target. 1

Alternative Consideration: Thiazide-Like Diuretic

• If the patient has no albuminuria or if hyperkalemia risk is prohibitive, consider adding a thiazide-like diuretic (chlorthalidone 12.5–25 mg daily) instead of an ACE inhibitor/ARB. 1, 7

• The ALLHAT trial showed that chlorthalidone was superior to both amlodipine and lisinopril in preventing heart failure in older high-risk hypertensive patients with reduced GFR, and was equally effective in preventing coronary heart disease and stroke. 7

• However, thiazide-like diuretics do not provide the renoprotective benefit of ACE inhibitors/ARBs in albuminuric CKD, so this option is less preferred if albuminuria is present. 1, 7

Common Pitfalls to Avoid

• Do not withhold ACE inhibitor/ARB therapy solely because the patient is African-American; the AASK trial definitively showed renal benefit in this population, particularly with proteinuria. 2, 3

• Do not discontinue the ACE inhibitor/ARB for a creatinine rise <30%; this reflects the intended hemodynamic effect and is acceptable. 1

• Do not continue spironolactone 100 mg daily without a clear indication (resistant hypertension or heart failure with reduced ejection fraction), as the dose is high for stage 3b CKD and the risk-benefit ratio is unfavorable. 6

• Do not apply a blood pressure target <120 mmHg to routine office measurements; this target requires standardized automated measurement and is not appropriate for typical clinic readings. 1

Follow-Up and Monitoring Schedule

• Schedule a clinic visit 2–4 weeks after initiating the ACE inhibitor/ARB to check serum creatinine, potassium, and blood pressure. 1, 2

• If potassium rises to 5.5–6.0 mEq/L, reduce spironolactone to 25 mg daily or discontinue it; if potassium >6.0 mEq/L, discontinue spironolactone immediately and consider a potassium binder (sodium zirconium cyclosilicate or patiromer) to allow continuation of the ACE inhibitor/ARB. 5

• Once the blood pressure target is achieved and electrolytes are stable, follow up every 3–6 months with monitoring of eGFR, serum creatinine, potassium, and urine albumin-to-creatinine ratio. 1

Patient Education: Sick-Day Management

• Instruct the patient to hold or reduce the ACE inhibitor/ARB, amlodipine, and spironolactone during acute illnesses with vomiting, diarrhea, or reduced oral intake to prevent volume depletion, acute kidney injury, and hyperkalemia. 1

• Teach the patient to watch for symptoms of hypotension (fatigue, light-headedness, dizziness) and hyperkalemia (muscle weakness, palpitations, nausea). 1