What are the guidelines for antihypertensive therapy in patients with Chronic Kidney Disease (CKD) stage 5 and a Glomerular Filtration Rate (GFR) of less than 10 milliliters per minute (ml/min)?

Antihypertensive Therapy in CKD Stage 5 (GFR <10 mL/min)

For patients with CKD stage 5 and GFR <10 mL/min, ACE inhibitors or ARBs remain the preferred first-line antihypertensive agents when proteinuria is present, with a target blood pressure <130/80 mmHg, though evidence is limited in this advanced stage and careful monitoring for hyperkalemia and acute kidney injury is essential. 1

Blood Pressure Targets

• Target BP <130/80 mmHg is reasonable for CKD stages 4-5 not on dialysis, though this recommendation is based on extrapolation from earlier CKD stages rather than direct trial evidence. 1
• The KDIGO 2019 commentary acknowledges insufficient high-quality data for specific BP targets in CKD stages 4 and 5, as most trials including SPRINT excluded patients with advanced CKD (eGFR <20 mL/min). 1
• More intensive BP lowering in advanced CKD may accelerate the need for kidney replacement therapy in some patients, particularly older individuals with low diastolic BP from arterial stiffness. 1
• The risk of acute kidney injury is substantially higher in CKD stages 4-5 compared to earlier stages, requiring cautious BP reduction. 1

First-Line Antihypertensive Selection

ACE Inhibitors or ARBs

• ACE inhibitors or ARBs are recommended as first-line therapy when moderate-to-severe albuminuria is present, even in advanced CKD. 1
• These agents provide renoprotection beyond BP lowering through reduction of intraglomerular pressure and proteinuria. 1, 2
• For lisinopril specifically in patients with GFR <10 mL/min or on hemodialysis, the FDA-approved initial dose is 2.5 mg once daily, with careful up-titration as tolerated to a maximum of 40 mg daily. 3
• For patients with creatinine clearance 10-30 mL/min, reduce the initial ACE inhibitor dose to half the usual recommended dose. 3
• ARBs may cause less hyperkalemia than ACE inhibitors in patients with eGFR <60 mL/min, though both require close monitoring. 1

Critical Monitoring Requirements

• Consider reducing the ACE inhibitor/ARB dose or discontinuing if creatinine rises >30% from baseline or if hyperkalemia develops. 1
• Diuretic-induced intravascular volume depletion is the most common avoidable reason for creatinine elevation with RAS inhibitors. 1
• The initial decline in GFR after starting ACE inhibitors/ARBs is attributable to disordered autoregulation and does not necessarily indicate treatment failure. 1
• Check serum potassium and creatinine within 5-7 days after initiating or adjusting RAS inhibitor doses in advanced CKD. 1

Second and Third-Line Agents

Diuretics

• Loop diuretics are typically required in CKD stage 5 for volume control, as thiazide diuretics lose efficacy at GFR <30 mL/min. 1
• Volume control with loop diuretics may be needed in patients with signs of volume overload and in those with nephrotic-range proteinuria. 1
• Chlorthalidone remains effective even in stage 4 CKD and can be considered for resistant hypertension. 4

Calcium Channel Blockers

• Long-acting dihydropyridine calcium channel blockers are reasonable second-line agents and can be used at any level of kidney function. 1, 4
• CCBs do not require dose adjustment based on renal function and carry lower risk of hyperkalemia compared to RAS inhibitors. 1
• Third-generation DHPs like manidipine may have additional beneficial effects on intrarenal hemodynamics and proteinuria compared to older agents. 2

Beta-Blockers

• Beta-blocker use in advanced CKD may be associated with higher risk of heart failure and death, particularly in early CKD stages, though they remain indicated for specific cardiac conditions. 5
• Use beta-blockers when there are specific cardiovascular indications (heart failure with reduced ejection fraction, post-MI, atrial fibrillation) rather than as routine antihypertensive therapy. 5

Multiple Drug Regimens

• Most patients with CKD stage 5 require 3-4 antihypertensive medications to achieve BP targets. 1, 6
• A rational combination approach: ACE inhibitor or ARB + loop diuretic + long-acting CCB, with addition of beta-blocker or other agents as needed. 1, 2
• Dietary sodium restriction to <2 grams daily is essential to maximize effectiveness of antihypertensive therapy and reduce medication requirements. 4, 6

Special Considerations for Advanced CKD

Hyperkalemia Management

• Newer potassium binders (patiromer, sodium zirconium cyclosilicate) can enable continuation of RAS inhibitors in patients who develop hyperkalemia. 1
• If potassium >5.5 mEq/L, halve the dose of RAS inhibitors and closely monitor; if >6.0 mEq/L, discontinue RAS inhibitors temporarily. 1
• Avoid potassium-sparing diuretics (spironolactone, amiloride, triamterene) when GFR <30 mL/min due to prohibitive hyperkalemia risk. 1

Patients Already on Dialysis

• For patients on hemodialysis with no residual renal function, standard antihypertensive dosing can be used without renal dose adjustment, though timing relative to dialysis sessions matters. 1
• Peritoneal dialysis patients with residual renal function should preferentially receive ACE inhibitors or ARBs to preserve remaining kidney function. 1

Common Pitfalls to Avoid

• Do not discontinue ACE inhibitors/ARBs prematurely when creatinine rises <30%, as this initial rise is expected and does not indicate harm. 1
• Avoid relying on serum creatinine alone; always calculate eGFR using validated equations (MDRD or CKD-EPI) that account for age, sex, and body size. 1
• Do not prescribe thiazide diuretics as monotherapy when GFR <30 mL/min, as they are ineffective at this level of renal function. 1
• Avoid NSAIDs entirely, as they cause sodium retention, worsen renal function, and increase hyperkalemia risk with RAS inhibitors. 1, 6
• Do not combine ACE inhibitors with ARBs routinely, as this increases adverse events without clear benefit in advanced CKD. 1