What is the use of Azathioprine in Interstitial Lung Disease (ILD) with Non-Specific Interstitial Pneumonia (NSIP) in a patient with Impaired Renal Function (creatinine clearance 30ml/min)?

From the Guidelines

Azathioprine should be used with caution in patients with non-specific interstitial pneumonia (NSIP) who have impaired renal function with a creatinine clearance of 30 ml/min, and the most recent guideline from the American College of Rheumatology (ACR) and American College of Chest Physicians (CHEST) supports its use as a first-line option across diseases, including NSIP 1. For such patients, I recommend starting at a reduced dose of 0.5-1 mg/kg/day (approximately 25-50 mg daily), which is about 50% of the standard dose. Close monitoring of complete blood counts and liver function tests should be performed weekly for the first month, then biweekly for the second month, and monthly thereafter. Dose adjustments should be made gradually, with increases of no more than 25 mg every 2-4 weeks based on tolerance and response, while not exceeding 1.5 mg/kg/day in this renal function range. Some key points to consider when using azathioprine in patients with impaired renal function include:

• Azathioprine is primarily metabolized by the liver, but some metabolites are excreted by the kidneys, which explains the need for dose reduction in renal impairment 1.
• Patients should be monitored for signs of myelosuppression, hepatotoxicity, and infection, which may occur more frequently with reduced renal function.
• Consider checking thiopurine methyltransferase (TPMT) activity before initiating therapy, as genetic variations can affect azathioprine metabolism and toxicity risk, especially in renally impaired patients 1. It is also important to note that the 2023 ACR/CHEST guideline for the treatment of interstitial lung disease in people with systemic autoimmune rheumatic diseases supports the use of azathioprine as a first-line option across diseases, although in SSc-ILD, azathioprine was considered an “additional option” rather than “preferred” therapy because of limited evidence of effectiveness relative to other therapies in SSc-ILD 1.

From the FDA Drug Label

Use in Renal Dysfunction: Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of AZASAN or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses.

The use of azathioprine in patients with renal dysfunction and a creatinine clearance of 30ml/min may require dose reduction due to the potential for delayed clearance of the drug or its metabolites. However, the exact dose reduction for a patient with this level of renal impairment is not specified in the label.

• Key considerations:
  • Renal dysfunction may affect the clearance of azathioprine
  • Dose reduction may be necessary to avoid toxicity
  • Patients with renal impairment should be monitored closely for signs of toxicity 2
• Main idea: Azathioprine dose reduction may be necessary in patients with significant renal impairment.

From the Research

Azathioprine in ILD NSIP with Creatinine Clearance 30ml/min

• The use of azathioprine in patients with interstitial lung disease (ILD) and reduced renal function, such as a creatinine clearance of 30ml/min, requires careful consideration of the potential risks and benefits.
• According to a study on azathioprine for connective tissue disease-associated interstitial lung disease 3, azathioprine can stabilize or improve lung function in patients with ILD, but early drug intolerance is frequent.
• However, there is limited information available on the use of azathioprine in patients with ILD and significant renal impairment, such as a creatinine clearance of 30ml/min.
• A study on the estimation of creatinine clearance in patients with unstable renal function 4 provides a method for estimating creatinine clearance without the need for a urine specimen, which may be useful in patients with ILD and renal impairment.
• Another study on the treatment of myositis-related interstitial lung disease with azathioprine and mycophenolate mofetil 5 suggests that azathioprine can improve lung function and reduce the prednisone dose in patients with myositis-related ILD.
• A review of interstitial lung disease 6 highlights the importance of individualized treatment approaches for patients with ILD, taking into account the underlying cause of the disease, the severity of lung involvement, and the presence of comorbidities such as renal impairment.

Dosage Adjustment and Monitoring

• In patients with reduced renal function, such as a creatinine clearance of 30ml/min, the dosage of azathioprine may need to be adjusted to minimize the risk of toxicity.
• Close monitoring of renal function, liver function, and blood counts is essential in patients with ILD and renal impairment who are treated with azathioprine 7, 3.
• The use of azathioprine in patients with ILD and significant renal impairment should be carefully weighed against the potential benefits, and alternative treatment options should be considered if necessary.