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 35ml/min)?

From the Guidelines

Azathioprine should be used with caution in patients with non-specific interstitial pneumonia (NSIP) who have reduced renal function with a creatinine clearance of 35 ml/min, as recommended by the 2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) guideline for the treatment of interstitial lung disease in people with systemic autoimmune rheumatic diseases 1. The recommended starting dose should be reduced to 50% of the standard dose (typically 0.5-1 mg/kg/day instead of the usual 1-2 mg/kg/day) with careful monitoring. Some key points to consider when using azathioprine in this context include:

• Dose adjustments should be made based on clinical response and laboratory parameters.
• Regular monitoring of complete blood count, liver function tests, and renal function is essential, with testing recommended weekly for the first month, then biweekly for the second and third months, and monthly thereafter.
• Patients should be monitored for signs of bone marrow suppression, which is more likely with reduced renal function as azathioprine metabolites accumulate.
• The medication should be immediately discontinued if severe cytopenias develop.
• This cautious approach is necessary because azathioprine and its metabolites are partially eliminated by the kidneys, and impaired renal function leads to increased drug exposure and potential toxicity.
• Concurrent allopurinol use should be strictly avoided as it inhibits azathioprine metabolism and dramatically increases toxicity risk, requiring at least a 75% dose reduction if absolutely necessary to use together 1. It's also important to note that azathioprine is conditionally recommended as a first-line ILD treatment option for people with SARD-ILD, including those with NSIP, according to the 2023 ACR/CHEST guideline 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 patient has a creatinine clearance of 35ml/min, indicating renal dysfunction.

• The dose of azathioprine should be lowered in patients with renal dysfunction.
• However, the exact dose reduction for a patient with a creatinine clearance of 35ml/min is not specified in the label.
• Therefore, the dose of azathioprine in a patient with ILD NSIP and a creatinine clearance of 35ml/min should be cautiously adjusted and monitored closely for signs of toxicity 2.

From the Research

Azathioprine in ILD NSIP with Creatinine Clearance 35ml/min

• The use of azathioprine in patients with interstitial lung disease (ILD) and nonspecific interstitial pneumonia (NSIP) pattern has been studied, particularly in the context of myositis-related ILD 3.
• A study published in 2019 found that azathioprine treatment was associated with improved forced vital capacity (FVC) % predicted and diffusing capacity of the lungs for carbon monoxide (Dlco) % predicted, as well as a lower prednisone dose in patients with myositis-related ILD 3.
• However, the study did not specifically address the use of azathioprine in patients with a creatinine clearance of 35ml/min.
• Another study published in 2002 discussed the estimation of creatinine clearance in patients with unstable renal function, which may be relevant to patients with ILD and impaired renal function 4.
• The study found that creatinine clearance can be estimated using a formula that takes into account the patient's age, gender, height, weight, and serum creatinine concentration, without the need for a urine specimen 4.
• In terms of immunosuppressive therapy for ILD, mycophenolate mofetil (MMF) is often used as a first-line treatment, particularly in patients with connective tissue disease-associated ILD 5, 6.
• The use of azathioprine in combination with MMF has not been extensively studied in patients with ILD and NSIP pattern, particularly in those with impaired renal function.
• Further research is needed to determine the safety and efficacy of azathioprine in patients with ILD and NSIP pattern, particularly in those with a creatinine clearance of 35ml/min.

Key Considerations

• Azathioprine may be associated with improved lung function and reduced prednisone dose in patients with myositis-related ILD 3.
• Estimation of creatinine clearance is important in patients with unstable renal function, and can be done using a formula that takes into account the patient's age, gender, height, weight, and serum creatinine concentration 4.
• MMF is often used as a first-line treatment for ILD, particularly in patients with connective tissue disease-associated ILD 5, 6.
• The use of azathioprine in combination with MMF has not been extensively studied in patients with ILD and NSIP pattern, particularly in those with impaired renal function.