Do ACE inhibitors cause metabolic acidosis? Understanding the Mechanism

October 12, 2025 •

4 min read

According to numerous case reports, ACE inhibitors have been documented to cause a form of hyperkalemic, hyperchloremic metabolic acidosis, particularly in patients with predisposing risk factors such as chronic kidney disease or diabetes. For those on this medication class, understanding the mechanism behind whether ACE inhibitors cause metabolic acidosis is crucial for proactive health management.

Quick Summary

ACE inhibitors can cause a type of metabolic acidosis by disrupting the renin-angiotensin-aldosterone system. This interference leads to hypoaldosteronism, which in turn impairs the kidney's ability to excrete acid and potassium, causing an electrolyte imbalance.

Key Points

Hypoaldosteronism: ACE inhibitors can induce hypoaldosteronism by blocking the synthesis of angiotensin II, a key signal for aldosterone production.
Type IV Renal Tubular Acidosis: The resulting low aldosterone levels can cause Type IV RTA, a condition characterized by hyperkalemia and a non-anion gap hyperchloremic metabolic acidosis.
Risk Factors: The risk is significantly higher in patients with pre-existing conditions like chronic kidney disease (CKD), diabetes, or those also on potassium-sparing diuretics.
Monitoring is Key: Regular monitoring of serum potassium and renal function is critical for early detection and management of this side effect.
Management: Treatment can include adjusting medication dosage, dietary changes, and, in severe cases, using diuretics or discontinuing the ACE inhibitor.
Preoperative Risk: Even patients with seemingly normal kidney function may be at risk during periods of physiological stress, such as surgery, due to the inhibited RAAS response.

The Renin-Angiotensin-Aldosterone System (RAAS) and Kidney Function

To understand how ACE inhibitors can lead to metabolic acidosis, one must first grasp the normal function of the renin-angiotensin-aldosterone system (RAAS). The RAAS is a hormone system that regulates blood pressure, fluid balance, and electrolyte balance. A key component of this system is aldosterone, a steroid hormone produced by the adrenal glands. Under normal circumstances, aldosterone acts on the distal tubules and collecting ducts of the kidneys, promoting the reabsorption of sodium and water while simultaneously stimulating the secretion of potassium and hydrogen ions ($H^+$).

This regulated secretion of $H^+$ is fundamental to maintaining the body's acid-base balance. Angiotensin II, a potent vasoconstrictor, is the primary stimulus for aldosterone secretion. The intricate balance of this system is essential for proper kidney function and overall physiological stability.

The Role of ACE Inhibitors in Causing Acidosis

Angiotensin-converting enzyme (ACE) inhibitors disrupt this delicate balance by blocking the enzyme responsible for converting angiotensin I to angiotensin II. This pharmacological action has several downstream effects, with a direct consequence being reduced aldosterone levels.

Mechanism of Hypoaldosteronism

When ACE is inhibited, the production of angiotensin II is significantly curtailed. Because angiotensin II is the main driver of aldosterone secretion, its suppression leads to a state of hyporeninemic hypoaldosteronism. This is the central mechanism by which ACE inhibitors interfere with the body's electrolyte and acid-base regulation.

Resulting Hyperkalemia and Metabolic Acidosis

With low levels of aldosterone, the kidney's collecting ducts lose their primary signal to excrete potassium and $H^+$. This impairment results in two key physiological changes:

Hyperkalemia: Elevated levels of potassium ($K^+$) build up in the blood.
Type IV Renal Tubular Acidosis (RTA): The kidney's inability to excrete $H^+$ leads to a retention of acid, causing a non-anion gap hyperchloremic metabolic acidosis.

This specific combination of hyperkalemia and a non-anion gap metabolic acidosis is the hallmark of Type IV RTA, and it is a well-documented adverse effect of RAAS-inhibiting drugs.

Identifying Risk Factors for ACE Inhibitor-Induced Acidosis

While ACE inhibitor-induced metabolic acidosis is a known risk, it is not a universal outcome. Several factors can increase a patient's susceptibility to this side effect. These include:

Chronic Kidney Disease (CKD): Patients with pre-existing kidney impairment have a reduced capacity to manage electrolyte imbalances, making them highly vulnerable.
Diabetes Mellitus: This condition is a significant risk factor for Type IV RTA, and the use of ACE inhibitors in diabetic patients exacerbates the risk.
Combination Therapies: Concurrently using other drugs that affect potassium or renal function, such as potassium-sparing diuretics or non-steroidal anti-inflammatory drugs (NSAIDs), significantly increases the risk of hyperkalemia and acidosis.
Preoperative or Stressful Conditions: Stressful situations, such as surgery, can disrupt the body's normal steroid response, which, when combined with the effect of an ACE inhibitor, can trigger acute hyperkalemia and acidosis.

Monitoring and Management Strategies

Due to the risks, diligent monitoring is essential for patients on ACE inhibitor therapy, particularly those with underlying risk factors. This includes:

Routine Electrolyte Monitoring: Regular blood tests to check potassium levels, especially after initiating or adjusting the dose of an ACE inhibitor.
Renal Function Assessment: Measuring serum creatinine and estimated glomerular filtration rate (eGFR) is necessary to monitor kidney health.
Clinical Vigilance: Watch for signs and symptoms such as muscle weakness, fatigue, or an irregular heartbeat, which can indicate hyperkalemia.

Management strategies for addressing ACE inhibitor-induced acidosis often involve a combination of interventions:

Medication Review: Evaluate and potentially discontinue other medications that contribute to hyperkalemia, such as potassium-sparing diuretics or NSAIDs.
Dietary Modification: A low-potassium diet may be recommended to help manage serum potassium levels.
Drug Discontinuation or Dose Adjustment: In cases of moderate to severe hyperkalemia or acidosis, the ACE inhibitor dose may be reduced or the drug temporarily or permanently stopped.
Medical Intervention: For persistent or severe cases, specific therapies may be required. This could include the use of loop diuretics, such as furosemide, which can promote potassium and hydrogen excretion to compensate for low aldosterone levels. In some instances, mineralocorticoid replacement therapy with fludrocortisone may be necessary.

Comparison of ACE Inhibitor-Induced Type IV RTA and Common Side Effects


Feature	ACE Inhibitor-Induced Type IV RTA	Common ACE Inhibitor Side Effects (e.g., Cough)
Mechanism	Inhibition of RAAS, leading to hypoaldosteronism.	Accumulation of bradykinin in the respiratory tract.
Symptom Profile	Electrolyte Imbalance: Hyperkalemia, non-anion gap metabolic acidosis. Symptoms: Fatigue, muscle weakness, potential for cardiac arrhythmias.	Respiratory: Dry, persistent hacking cough. Cardiovascular: Dizziness, hypotension.
Onset	Can be insidious, becoming apparent with electrolyte monitoring, or acute during stress.	Often starts within days to weeks of beginning therapy.
Risk Factors	Underlying conditions like CKD and diabetes, combined use of certain medications.	More common in certain populations, but can occur in anyone.
Treatment	Discontinuation, dose adjustment, dietary changes, or specific medical therapies like furosemide or fludrocortisone.	Can resolve with dose reduction or switching to an angiotensin receptor blocker (ARB).

Conclusion

While ACE inhibitors are highly effective and widely used medications for conditions like hypertension and heart failure, their potential to cause metabolic acidosis should not be overlooked. The mechanism is a clear result of their impact on the RAAS, leading to a state of hypoaldosteronism that disrupts the kidney's acid and potassium balance. The risk is particularly elevated in patients with underlying chronic kidney disease or diabetes. With proper patient selection, careful monitoring of electrolytes and renal function, and awareness of risk factors, clinicians can safely manage patients and address adverse effects should they arise. Ultimately, managing ACE inhibitor-induced acidosis and hyperkalemia involves a collaborative effort between patient and healthcare provider, focusing on minimizing risk and optimizing therapeutic benefits.

For more in-depth information on managing electrolyte imbalances caused by RAAS inhibitors, the American Kidney Fund offers resources on metabolic acidosis.

Frequently Asked Questions

ACE inhibitors block the conversion of angiotensin I to angiotensin II, which reduces the production of aldosterone. This leads to impaired excretion of potassium and hydrogen ions in the kidneys, resulting in hyperkalemia and a form of metabolic acidosis called Type IV Renal Tubular Acidosis.

Significant metabolic acidosis from ACE inhibitors is relatively uncommon but the risk increases substantially for patients with specific predisposing conditions like chronic kidney disease (CKD) or diabetes.

A mild case may be asymptomatic, but more severe cases can present with symptoms related to hyperkalemia, such as muscle weakness, fatigue, and potentially dangerous cardiac arrhythmias. Regular blood tests are the most reliable way to monitor for the condition.

Unlike the common dry cough caused by bradykinin accumulation, metabolic acidosis results from the inhibition of the renin-angiotensin-aldosterone system (RAAS) and is characterized by electrolyte imbalances (hyperkalemia and non-anion gap acidosis).

The decision depends on the severity and underlying risk factors. For mild cases, dietary adjustments or managing other medications may be sufficient. Your doctor may also lower the dose. For more severe cases, discontinuation may be necessary.

Management strategies include dietary modifications (low-potassium diet), dose adjustments, discontinuing the ACE inhibitor, or using medications like loop diuretics (e.g., furosemide) or mineralocorticoid replacement therapy.

Yes, chronic kidney disease (CKD), diabetes mellitus, and concomitant use of potassium-sparing diuretics or NSAIDs are all significant risk factors that increase the likelihood of developing ACE inhibitor-induced metabolic acidosis.

No, you should never stop or change your medication without consulting your healthcare provider first. Abrupt discontinuation can be harmful. It's essential to discuss your concerns and symptoms with your doctor, who can perform the necessary blood tests and determine the best course of action.