What is the recommended management for a patient with Chronic Kidney Disease (CKD) and Heart Failure with Reduced Ejection Fraction (HFrEF)?

Management of CKD with HFrEF

Patients with CKD and HFrEF should receive quadruple guideline-directed medical therapy (GDMT) consisting of an SGLT2 inhibitor, beta-blocker, ARNI (or ACE inhibitor/ARB if ARNI not feasible), and mineralocorticoid receptor antagonist, with diuretics as needed for congestion, as this combination significantly reduces mortality and hospitalization even in the presence of moderate-to-severe kidney disease. 1, 2

Core Pharmacologic Therapy

SGLT2 Inhibitors (First Priority)

• Initiate an SGLT2 inhibitor (dapagliflozin or empagliflozin) in all patients with eGFR ≥20 mL/min/1.73 m², regardless of diabetes status 1
• Continue SGLT2 inhibitor even if eGFR falls below 20 mL/min/1.73 m² after initiation, unless not tolerated or kidney replacement therapy is started 1
• Expect a modest initial eGFR decline (3-10%) which is hemodynamically mediated and does not indicate harm 1
• Temporarily withhold during prolonged fasting, surgery, or critical illness due to ketosis risk 1

Renin-Angiotensin System Inhibition

• Start with ARNI (sacubitril/valsartan) for NYHA class II-III symptoms to reduce morbidity and mortality 1, 2
• ARNI is preferred over ACE inhibitors or ARBs and can be used safely down to eGFR 20 mL/min/1.73 m² 1, 3
• If ARNI not feasible, use ACE inhibitor as first alternative; ARB if ACE inhibitor causes cough or angioedema 1
• Continue RAS inhibition even when eGFR falls below 30 mL/min/1.73 m² 1
• Titrate to maximum tolerated dose, as trial benefits were achieved at target doses 1

Beta-Blockers

• Use one of three evidence-based beta-blockers: bisoprolol, carvedilol, or metoprolol succinate 1, 2
• Beta-blockers are safe and effective across all CKD stages, including dialysis patients 3, 4
• Start at low doses and titrate gradually to target doses 2
• No dose adjustment needed for renal impairment except bisoprolol may accumulate, but still titrate to target dose based on clinical response 5

Mineralocorticoid Receptor Antagonists

• Initiate MRA (spironolactone or eplerenone) if eGFR >30 mL/min/1.73 m² and potassium <5.0 mEq/L 1
• Start with low dose (spironolactone 12.5-25 mg daily or eplerenone 25 mg daily) 1, 5
• For patients with type 2 diabetes and eGFR >25 mL/min/1.73 m², consider nonsteroidal MRA (finerenone) if albuminuria persists despite RAS inhibitor 1

Diuretics

• Use loop diuretics (furosemide, bumetanide, or torsemide) for fluid retention to improve symptoms 1
• Torsemide has longest duration of action (12-16 hours) and may be preferred in CKD 1
• Consider sequential nephron blockade (metolazone plus loop diuretic) for refractory congestion 1

Implementation Strategy

Initiation Approach

• Start multiple medications simultaneously at low doses rather than sequentially, then uptitrate over 6-12 weeks 2
• This rapid implementation approach reduces death and hospitalization compared to traditional sequential uptitration 1

Monitoring Parameters

• Check blood pressure, serum creatinine, and potassium within 2-4 weeks of initiating or increasing RAS inhibitor dose 1
• Monitor natriuretic peptides (BNP or NT-proBNP) and albuminuria (UACR) to assess disease progression 1
• Assess symptoms, functional capacity, heart rate, and rhythm regularly 2

Managing Common Complications

Acute eGFR Decline

• Tolerate eGFR decreases ≤30% after RAS inhibitor initiation—do not discontinue prematurely 1
• If >30% decline, ensure euvolemia by adjusting diuretics, discontinue nephrotoxic agents, and evaluate alternative causes 1
• Continue ACE inhibitor/ARB unless creatinine rises >30% within 4 weeks of initiation 1

Hyperkalemia Management (K+ >5.0 mEq/L)

• Recheck elevated potassium before making therapeutic changes 1
• Implement low-potassium diet and discontinue potassium supplements 1
• Consider potassium binders (patiromer or sodium zirconium cyclosilicate) to facilitate continued use of life-saving therapies rather than stopping medications 1
• SGLT2 inhibitors lower hyperkalemia risk when combined with MRA 1
• ARNI carries lower hyperkalemia risk than ACE inhibitors when used with MRA 1

Hypotension

• Reduce or discontinue RAS inhibitor only if symptomatic hypotension occurs despite medical management 1
• Consider reducing diuretic doses in non-congested patients when initiating ARNI due to enhanced natriuresis 6

Critical Pitfalls to Avoid

Underutilization of Therapy

• Do not withhold evidence-based therapies solely based on CKD presence 2, 4
• Patients with CKD are systematically undertreated despite proven efficacy in this population 7
• Most drug classes are safe and effective up to CKD stage 3B (eGFR ≥30 mL/min/1.73 m²) 4

Premature Discontinuation

• Do not stop medications for initial eGFR decline if clinical condition is stable or improving 1, 4
• Renal function often stabilizes over time, and drugs maintain clinical efficacy despite initial decline 4
• Hyperkalemia can usually be managed without stopping RAS inhibition 1

Contraindicated Combinations

• Avoid triple RAAS blockade (ACE inhibitor + ARB + direct renin inhibitor) due to excessive hyperkalemia risk 1
• Avoid NSAIDs as they worsen renal function and counteract GDMT benefits 2
• Avoid nondihydropyridine calcium channel blockers in low LVEF 1

Special Considerations for Advanced CKD

eGFR 20-30 mL/min/1.73 m² (Stage 4)

• SGLT2 inhibitors have proven safety and efficacy 4
• Continue RAS inhibition with close monitoring 1
• MRA generally not recommended below eGFR 30 mL/min/1.73 m² due to hyperkalemia risk 1

eGFR <20 mL/min/1.73 m² (Stage 5)

• Continue beta-blockers as they are effective across all CKD stages including dialysis 3, 4
• Evidence lacking for other HFrEF therapies at this stage 4
• Consider reducing or discontinuing RAS inhibitors to reduce uremic symptoms 1

Comorbid Type 2 Diabetes

• SGLT2 inhibitors provide dual cardiovascular and renal protection 1
• Nonsteroidal MRA (finerenone) recommended for persistent albuminuria despite maximum RAS inhibitor dose 1
• GLP-1 receptor agonists reasonable if BMI ≥30 kg/m² 1

Additional Therapies

Device Therapy

• ICD reasonable for asymptomatic ischemic cardiomyopathy with LVEF ≤30%, >40 days post-MI, on GDMT 1
• Cardiac resynchronization therapy reduces death and hospitalizations in CKD stage 3 3

Adjunctive Treatments

• Intravenous iron improves symptoms in CKD stage 3 and reduces HF hospitalizations by 44% in dialysis patients 3
• Cardiac rehabilitation improves functional capacity, quality of life, and mortality 1
• Sodium restriction reasonable for symptomatic patients to reduce congestion 1