Can Angiotensin-Converting Enzyme Inhibitors (ACE-I) and Hydrochlorothiazide cause Intrarenal Acute Kidney Injury (AKI) and Acute Tubular Necrosis (ATN)?

From the Guidelines

Yes, ACE inhibitors (ACE-i) and hydrochlorothiazide can potentially cause intrarenal acute kidney injury (AKI) and acute tubular necrosis (ATN) in certain clinical scenarios, particularly when used together in vulnerable patients. The most recent and highest quality study, published in 2024 1, emphasizes that ACE inhibitors and ARBs should be used with caution, as they can reduce intravascular volume, renal blood flow, and/or glomerular filtration, especially in patients with pre-existing kidney disease or those taking diuretics.

Key Considerations

• ACE inhibitors can lead to intrarenal AKI by reducing efferent arteriolar tone, which decreases glomerular filtration pressure, and this effect is particularly problematic in patients with bilateral renal artery stenosis, severe volume depletion, or when renal perfusion is compromised.
• Hydrochlorothiazide, a thiazide diuretic, can contribute to AKI through volume depletion and subsequent decreased renal perfusion.
• When these medications are used together, the risk increases, especially in vulnerable patients such as the elderly, those with pre-existing kidney disease, or during situations causing volume depletion like diarrhea, vomiting, or excessive sweating.
• ATN may develop as a consequence of prolonged renal hypoperfusion.

Monitoring and Management

• Patients taking these medications should maintain adequate hydration and have their kidney function and electrolytes monitored regularly.
• Temporary discontinuation of these medications is recommended during acute illnesses that may cause volume depletion.
• If signs of AKI develop (rising creatinine, decreased urine output), these medications should be promptly held and medical attention sought.
• The combined use of ACE inhibitors and ARBs should be avoided due to higher adverse event rates (hyperkalemia and/or AKI), as noted in clinical trials 1.

Clinical Decision Making

• The decision to use ACE inhibitors and hydrochlorothiazide should be based on a careful assessment of the individual patient's risk factors and the potential benefits and risks of these medications.
• Clinicians should be aware of the potential for AKI and ATN and monitor patients closely for signs of these complications.
• The use of these medications should be guided by the most recent clinical guidelines and evidence-based recommendations, such as those provided by the American Heart Association and the Kidney International 1.

From the FDA Drug Label

Hydrochlorothiazide also decreases the excretion of calcium and uric acid, may increase the excretion of iodide and may reduce glomerular filtration rate Metabolic toxicities associated with excessive electrolyte changes caused by hydrochlorothiazide have been shown to be dose-related. In patients with renal disease, plasma concentrations of hydrochlorothiazide are increased and the elimination half-life is prolonged

The combination of Angiotensin-Converting Enzyme Inhibitors (ACE-I) and Hydrochlorothiazide may cause Intrarenal Acute Kidney Injury (AKI) and Acute Tubular Necrosis (ATN) due to the potential reduction in glomerular filtration rate and excessive electrolyte changes associated with hydrochlorothiazide. However, the label does not directly address the combination of ACE-I and hydrochlorothiazide.

• The label only mentions that hydrochlorothiazide may reduce glomerular filtration rate.
• It also mentions that metabolic toxicities associated with excessive electrolyte changes have been shown to be dose-related.
• Additionally, in patients with renal disease, plasma concentrations of hydrochlorothiazide are increased and the elimination half-life is prolonged 2.

From the Research

Angiotensin-Converting Enzyme Inhibitors (ACE-I) and Hydrochlorothiazide

• The use of ACE inhibitors in patients with heart failure and renal insufficiency has been shown to slow the progression of renal disease, despite an initial rise in serum creatinine levels 3, 4.
• The combination of ACE inhibitors and diuretics, such as hydrochlorothiazide, is safe and well-tolerated, with a favorable clinical outcome 5.
• However, the use of ACE inhibitors and diuretics can lead to an increase in serum creatinine levels and a decrease in glomerular filtration rate (GFR), which can be a concern in patients with pre-existing renal insufficiency 3, 4.

Intrarenal Acute Kidney Injury (AKI) and Acute Tubular Necrosis (ATN)

• There is no direct evidence to suggest that ACE inhibitors and hydrochlorothiazide can cause intrarenal AKI and ATN.
• However, the use of ACE inhibitors and diuretics can lead to a decrease in renal function, which can increase the risk of AKI and ATN in patients with pre-existing renal insufficiency 3, 4.
• It is essential to monitor serum creatinine and potassium levels in patients with chronic kidney disease (CKD) who are prescribed ACE inhibitors and diuretics, as they are at a higher risk of developing hyperkalemia and worsening renal function 6.

Monitoring and Management

• Regular monitoring of serum creatinine and potassium levels is crucial in patients with CKD who are prescribed ACE inhibitors and diuretics 6.
• The use of ACE inhibitors and diuretics should be carefully managed in patients with pre-existing renal insufficiency, and the benefits and risks of treatment should be carefully weighed 3, 4.
• Patients with CKD should be closely monitored for signs of worsening renal function, and the dose of ACE inhibitors and diuretics should be adjusted accordingly 3, 4.