What is causing the rising tacrolimus (immunosuppressant) levels in a patient with Chronic Kidney Disease (CKD) stage 3 and persistent diarrhea after a norovirus infection?

From the Guidelines

The rising tacrolimus levels in this patient are likely caused by decreased tacrolimus clearance due to CKD stage 3 and persistent diarrhea after a norovirus infection, necessitating a dose reduction and close monitoring to prevent nephrotoxicity. The patient's CKD stage 3 is a significant factor, as tacrolimus metabolites are excreted renally, and impaired kidney function can lead to decreased clearance 1. Additionally, the persistent diarrhea following norovirus infection can damage intestinal mucosa, reducing the activity of CYP3A4 enzymes and P-glycoprotein, which normally limit tacrolimus absorption, and cause dehydration, further worsening kidney function and reducing tacrolimus clearance.

Key factors contributing to the rising tacrolimus levels include:

• Decreased renal clearance due to CKD stage 3
• Persistent diarrhea causing intestinal mucosa damage and dehydration
• Potential for nephrotoxicity with elevated tacrolimus levels

Management strategies should include:

• Tacrolimus dose reduction (typically by 30-50%) to prevent nephrotoxicity and maintain therapeutic levels
• More frequent drug level monitoring (every 3-5 days until stable) to ensure levels remain within the therapeutic range
• Ensuring adequate hydration to prevent dehydration and further kidney function decline
• Treating the underlying diarrhea with appropriate antidiarrheals if infectious causes have been ruled out
• Consultation with a transplant specialist or clinical pharmacist for precise dose adjustments based on the patient's specific clinical situation, considering the latest guidelines for tacrolimus use in patients with kidney dysfunction 1.

From the FDA Drug Label

5.5 Nephrotoxicity due to Tacrolimus and Drug Interactions Tacrolimus, like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Nephrotoxicity was reported in clinical trials [see Adverse Reactions (6. 1)]. Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). When tacrolimus is used concurrently with other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust doses of both tacrolimus and/or concomitant medications during concurrent use [see Drug Interactions (7.2)].

The rising tacrolimus levels in a patient with Chronic Kidney Disease (CKD) stage 3 and persistent diarrhea after a norovirus infection could be due to several factors, including:

• Nephrotoxicity: Tacrolimus can cause nephrotoxicity, which may lead to increased tacrolimus levels due to decreased renal function.
• Drug interactions: Concomitant use of other nephrotoxic drugs or CYP3A inhibitors may increase the risk of nephrotoxicity and rising tacrolimus levels.
• Diarrhea: Persistent diarrhea may lead to dehydration and decreased renal function, which can cause increased tacrolimus levels. It is essential to monitor renal function, tacrolimus blood concentrations, and adjust doses of tacrolimus and/or concomitant medications during concurrent use 2.

From the Research

Potential Causes of Rising Tacrolimus Levels

The patient's rising tacrolimus levels, despite being within normal limits, could be attributed to several factors, including:

• Severe diarrhea: As seen in the case report 3, severe diarrhea can lead to increased tacrolimus trough levels, potentially due to the destruction of intestinal epithelial cells and altered P-glycoprotein activity.
• Nephrotoxicity: Tacrolimus can cause nephrotoxicity, even at recommended concentrations 4, 5, 6, which may lead to increased serum creatinine levels and altered tacrolimus pharmacokinetics.
• Individual variability: Patients may exhibit individual variability in tacrolimus pharmacokinetics, making it essential to monitor trough levels closely 4.
• Drug interactions: Although not mentioned in the provided evidence, drug interactions could potentially affect tacrolimus levels.

Factors to Consider in CKD Stage 3 Patients

In patients with CKD stage 3, the following factors should be considered:

• Renal function: Impaired renal function can affect tacrolimus pharmacokinetics and increase the risk of nephrotoxicity 4, 6.
• Dose adjustments: Close monitoring of tacrolimus trough levels and adjustment of the dose as needed may be necessary to prevent nephrotoxicity 4, 6.

Monitoring and Management

To manage the patient's rising tacrolimus levels, the following steps can be taken:

• Close monitoring: Regular monitoring of tacrolimus trough levels, serum creatinine, and other relevant laboratory parameters is essential 4, 3, 6.
• Dose adjustments: Adjusting the tacrolimus dose based on trough levels and clinical response may be necessary to prevent nephrotoxicity and ensure optimal immunosuppression 4, 6.
• Management of diarrhea: Prompt treatment of diarrhea and monitoring of its resolution can help prevent further increases in tacrolimus levels 3.