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Calcineurin Inhibitors and Other Immunosuppressive Drugs and the Kidney


Objectives

This chapter will:

  • 1.

    Define potential mechanisms underlying the nephrotoxicity of immunosuppressive drugs in the intensive care unit (ICU).

  • 2.

    Analyze pharmacologic interactions among immunosuppressive agents and other drugs used in ICU patients.

  • 3.

    Evaluate clinical outcomes after adjustments or reductions in the immunosuppressive regimen.

Drug-induced nephrotoxicity can cause acute kidney injury (AKI) in patients in the intensive care unit (ICU). Drug toxicity may cause tubular damage (tubular cell apoptosis and necrosis), interstitial inflammation (interstitial nephritis), vascular injury (thrombotic microangiopathy), and alteration of tubular cell functions (i.e., decreased membrane transport, defective mitochondrial function, and increased levels of oxidative stress species). However, the progression from functional impairment to renal failure usually involves additional factors, such as metabolic disorders associated with diabetes, sepsis, hypovolemia, or infusion of contrast media.

Several drugs may be responsible for renal damage in ICU patients. These include antibiotics (aminoglycosides), antimycotic agents, and immunosuppressive drugs ( Box 219.1 ).

Box 219.1
Classification of Immunosuppressive Drugs

  • Glucocorticoids

  • Antimetabolites

    • Azathioprine

    • Mycophenolic acid

    • Methotrexate

  • Calcineurin inhibitors

    • Cyclophilin-binding drugs (e.g., cyclosporine)

    • FKBP12-binding drugs (e.g., tacrolimus)

  • mTOR inhibitors

    • Sirolimus

    • Everolimus

  • Monoclonal antibodies

    • Bevacizumab

    • Cetuximab

    • Panitumumab

    • Rituximab

  • Fusion proteins

    • Belatacept

  • Intravenous immune globulins

mTOR, Mammalian target of rapamycin.

Glucocorticoids

Glucocorticoids are used frequently to treat ICU patients because of their potent antiinflammatory effects. Despite their efficacy in combating inflammation, they are characterized by a broad range of toxic effects, such as hypertension, glucose intolerance, and cardiovascular disease, which contribute to an increased risk of premature death, particularly among renal transplant recipients, from atherosclerotic heart disease. Other reported toxic effects include lymphoproliferative disorders, dyslipidemia, weight gain with central obesity, peptic ulcer formation, pancreatitis, cataract formation, diabetes, osteoporosis with avascular necrosis of bone, growth retardation, and personality disorders. The role of corticosteroid therapy in increasing a patient's risk of life-threatening infections and metabolic abnormalities has been well established.

To avoid the development of the aforementioned complications, the drug dose should be tapered during the course of the disease. Tapering must be done carefully to avoid recurrence of the disease and presence of cortisol deficiency resulting from suppression of the hypothalamic-pituitary-adrenal axis during the period of steroid therapy. Because of the availability of combinations with other immunosuppressants, corticosteroids can be avoided in most patients or administered for only a short period at low dosage.

Azathioprine

Azathioprine is an antimetabolite, an imidazole derivate of 6-mercaptopurine. It has been used in clinical transplantation for more than 30 years. The most important side effects of this drug are thrombocytopenia and leukopenia. Azathioprine is converted to inactive 6-thiouric acid by xanthine oxidase. Because this enzyme is inhibited by allopurinol, this drug combination is contraindicated. In the presence of renal impairment, the azathioprine dose must be reduced by 75% when the creatinine clearance rate is between 10 and 50 mL/min and by 50% when it is less than 10 mL/min.

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