What are the antihypertensive options for patients with Chronic Kidney Disease (CKD) stage 4, characterized by Impaired Renal Function?

From the Guidelines

In patients with stage 4 chronic kidney disease (CKD), angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are the preferred first-line antihypertensive medications, as they have been shown to reduce the risk of kidney failure and major cardiovascular events 1. The choice of ACEI or ARB should be based on individual patient characteristics, such as the presence of diabetes and albuminuria.

• For patients with CKD and severely increased albuminuria, RASi (ACEi or ARB) is recommended as first-line therapy, regardless of the presence of diabetes 1.
• For patients with CKD and moderately increased albuminuria, RASi (ACEi or ARB) may be considered as first-line therapy, especially in those with diabetes 1. Some examples of ACEIs and ARBs that can be used in patients with stage 4 CKD include:
• Lisinopril (starting at 2.5-5 mg daily)
• Enalapril (2.5-5 mg daily)
• Losartan (25-50 mg daily)
• Irbesartan (75-150 mg daily) It is essential to start with lower doses and gradually adjust based on response and kidney function, while closely monitoring blood pressure, kidney function, and potassium levels 1. Additional antihypertensive agents, such as diuretics, calcium channel blockers, and beta-blockers, may be added as second-line therapy to achieve the target blood pressure of <130/80 mmHg, with individualization based on comorbidities and tolerance 1.
• Diuretics, such as loop diuretics (e.g., furosemide, torsemide), are preferred over thiazides due to their effectiveness in reduced kidney function.
• Calcium channel blockers, such as amlodipine, do not require dose adjustment in CKD and can be useful additions.
• Beta-blockers, such as metoprolol, may be beneficial, especially in patients with heart failure or coronary artery disease. It is crucial to avoid potassium-sparing diuretics and NSAIDs, which can worsen hyperkalemia and kidney function in patients with stage 4 CKD 1.

From the FDA Drug Label

In patients with creatinine clearance ≥ 10 mL/min and ≤ 30 mL/min, reduce the initial dose of lisinopril tablets to half of the usual recommended dose i.e., hypertension, 5 mg; The recommended initial dose for patients with creatinine clearance < 10 mL/min is 2.5 mg once daily For the primary endpoint and stroke, the effects of losartan in patient subgroups defined by age, gender, race and presence or absence of isolated systolic hypertension (ISH), diabetes, and history of cardiovascular disease (CVD) are shown The RENAAL study was a randomized, placebo-controlled, double-blind, multicenter study conducted worldwide in 1513 patients with type 2 diabetes with nephropathy

Antihypertensive options for patients with CKD stage 4 include:

• Lisinopril: The initial dose should be reduced to half of the usual recommended dose, which is 5 mg for hypertension. The dose can be titrated up to a maximum of 40 mg daily.
• Losartan: The drug label does not provide specific dosing recommendations for patients with CKD stage 4. However, the RENAAL study showed that losartan reduced the risk of doubling of serum creatinine, end-stage renal disease, and death in patients with type 2 diabetes and nephropathy. 2 3

From the Research

Antihypertensive Options for CKD Stage 4

• Angiotensin receptor blockers (ARBs) are a suitable option for managing hypertension in patients with CKD stage 4, as they have been shown to reduce blood pressure and provide renal protection 4.
• Specific ARBs such as irbesartan, losartan, telmisartan, and valsartan have been found to be effective in improving renal dysfunction in patients with CKD 4.
• Telmisartan has been shown to provide superior reductions in proteinuria compared to losartan, possibly due to its higher receptor affinity, longer plasma half-life, and higher lipophilicity 4.

Combination Therapies

• Combining an ARB with a calcium channel blocker (CCB) may be a more effective antihypertensive strategy than combining an ARB with a diuretic, as it can provide better blood pressure control and renal function preservation 5.
• The combination of losartan and controlled-release nifedipine has been shown to be superior to the combination of losartan and hydrochlorothiazide in terms of blood pressure control and renal function preservation 5.

Comparison of Antihypertensive Agents

• Losartan has been compared to amlodipine and lisinopril in terms of antihypertensive effect and tolerability, with losartan showing similar efficacy but superior tolerability 6.
• Losartan has been shown to decrease albumin excretion in hypertensive patients with non-diabetic nephropathy, whereas amlodipine did not have a significant effect 7.

Safety Considerations

• The use of combined therapy with an ACE inhibitor and an ARB should be approached with caution, as it can increase the risk of acute renal failure, particularly in patients with pre-existing renal dysfunction 8.