What are the guidelines for using Angiotensin-Converting Enzyme Inhibitors (ACEI)/Angiotensin Receptor Blockers (ARB) as Guideline-Directed Medical Therapy (GDMT) in patients with End-Stage Renal Disease (ESRD) on Hemodialysis (HD)?

From the Guidelines

The use of Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) in patients with End-Stage Renal Disease (ESRD) on hemodialysis is generally not recommended as standard Guideline-Directed Medical Therapy (GDMT), and should be used with extreme caution due to the risk of hyperkalemia and other adverse effects, as suggested by the most recent guidelines 1.

Key Considerations

• The European Society of Cardiology guidelines recommend the use of ACEIs and ARBs only if eGFR is >30 mL·min−1·1.73 m−2, while the American College of Cardiology Foundation/American Heart Association Guideline for the Management of Heart Failure suggests their use with caution in patients with creatinine >3 mg/dL 1.
• Close monitoring of renal function and potassium levels is required when using ACEIs and ARBs in patients with ESRD on hemodialysis, as the risk of hyperkalemia is heightened in this population 1.
• The potential benefits of ACEIs and ARBs may outweigh the risks in selected cases, such as patients with heart failure with reduced ejection fraction or significant proteinuria with residual kidney function 1.

Management Strategies

• If used, ACEIs and ARBs should be started at the lowest possible dose and titrated cautiously while monitoring blood pressure and potassium levels 1.
• Patients should be educated to avoid over-the-counter potassium supplements and potassium-based salt substitutes, limit intake of high-potassium food and beverages, and avoid medications that may increase the risk for hyperkalemia, such as nonsteroidal anti-inflammatory drugs 1.
• The use of potassium-binding agents, such as patiromer or SZC, may allow for the continuation and optimization of RAASi therapy in patients with hyperkalemia, but consideration of costs may influence their use in clinical practice 1.

From the FDA Drug Label

7.4 Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors. The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial enrolled 1448 patients with type 2 diabetes, elevated urinary-albumin-to-creatinine ratio, and decreased estimated glomerular filtration rate (GFR 30 to 89.9 mL/min), randomized them to lisinopril or placebo on a background of losartan therapy and followed them for a median of 2.2 years. Patients receiving the combination of losartan and lisinopril did not obtain any additional benefit compared to monotherapy for the combined endpoint of decline in GFR, end stage renal disease, or death, but experienced an increased incidence of hyperkalemia and acute kidney injury compared with the monotherapy group

The use of ACEI/ARB as GDMT in patients with ESRD on HD is not directly supported by the provided drug labels. However, the labels do provide information on the risks associated with RAS inhibitors in patients with renal impairment.

• The labels warn against the use of dual RAS inhibitors due to increased risks of hypotension, syncope, hyperkalemia, and changes in renal function.
• The VA NEPHRON-D trial found no additional benefit to using two RAS inhibitors concomitantly in patients with decreased GFR, and instead found an increased incidence of hyperkalemia and acute kidney injury. Given the lack of direct information on the use of ACEI/ARB in patients with ESRD on HD, and considering the potential risks associated with RAS inhibitors in patients with renal impairment, a conservative clinical decision would be to avoid the use of ACEI/ARB as GDMT in patients with ESRD on HD, or to use them with extreme caution and close monitoring of blood pressure, renal function, and electrolytes 2.

From the Research

Guidelines for Using ACEI/ARB as GDMT in Patients with ESRD on HD

• The use of Angiotensin-Converting Enzyme Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB) in patients with End-Stage Renal Disease (ESRD) on Hemodialysis (HD) is associated with a decrease in morbidity and mortality by reducing mean arterial pressure, aortic pulse wave velocity, and aortic systolic pressure augmentation, as well as left ventricular hypertrophy (LVH) and probably reduction of C-reactive protein (CRP) and oxidant stress 3.
• However, the use of ACEI/ARB in anuric HD patients is associated with an increased risk of hyperkalemia, with a significant increase in serum potassium concentrations and a higher percentage of patients developing mild and severe hyperkalemia 4.
• A meta-analysis suggests that combination therapy with ACEI and ARB can be used in patients with diabetic nephropathy, but should be used with caution in those with decreased renal function, especially with severe renal failure 5.
• ACE inhibitors have been shown to decrease mortality in patients undergoing long-term hemodialysis therapy, with a risk reduction of 52% compared to those not treated with ACE inhibitors 6.
• The combination of ACEI/ARB and calcium channel blockers has been shown to have a greater reduction in systolic blood pressure compared to ACEI/ARB monotherapy, but does not provide additional renoprotective benefit beyond what can be achieved with ACEI/ARB monotherapy 7.

Potential Risks and Considerations

• Hyperkalemia is a significant risk associated with the use of ACEI/ARB in HD patients, particularly in anuric patients 4.
• Anaphylactoid reactions with AN69 membranes are a potential risk with ACE inhibitors 3.
• Aggravation of renal anemia is a potential risk with the use of ACEI/ARB in HD patients 3.
• Close monitoring of serum potassium levels and blood pressure is necessary when using ACEI/ARB in HD patients 4.