Adverse effects associated with the use of FK 506. (1991)

Cyclosporine (CyA)-based immunosuppression significantly enhanced both patient and graft survival in all solid organ transplants. when compared to the era of azathioprine and steroids. The widespread use of CyA has spawned a growing body of experience delineating the side effects of CyA use, which was apparent in the first reports on human patients.1 Prior to the utilization of monitoring techniques, renal dysfunction was often used as a guideline to effective CyA dosing.2 More recently, monitoring of CyA trough levels has been used to guide CyA dosing,3 although some patients manifest toxicity at “therapeutic levels.” while others do not manifest any side effects at levels considered “excessive”.4 This has held true, regardless of the development of a number of different assay systems monitoring either parent CyA drug or its metabolites.

Nephrotoxicity remains the principle limiting side effect of CyA, and has been reported to occur in more than 50% of patients. Unfortunately, the mechanism(s) of CyA nephrotoxicity have not been clearly defined. Hypertension (40% to 60%), hyperkalemia, hirsutism (60% to 80%), gingival hypertrophy, hepatotoxicity (40% to 60%), and tremors are relatively common side effects of CyA (reviewed by Thiru5).

Malignant complications include a higher incidence of posttransplant lymphoproliferative disease (PTLD), as well as a variety of skin cancers, including Kaposi’s sarcoma. PTLD is an abnormality of lymphocyte proliferation in a setting of an immunosuppressed patient. The spectrum of PTLD can range from a benign lymphoid proliferation, such as a mononucleosis syndrome, to a frankly malignant lymphoid tumor. PTLD has been associated with all types of immunosuppressive therapy. The incidence of PTLD in the CyA era is generally estimated between 2% and 4%.7 Most (90% to 95%) of PTLD are B cell in origin, and most are associated with integration of Epstein-Barr virus (EBV) DNA into the genome of the B cell. A smaller number of PTLD are T cell in origin.

Because of the relatively high percentages of patients developing rejection on CyA therapy (estimated at 50% to 70%), multiple drug combinations have been utilized to prevent rejection, while minimizing toxicities. The sequelae of overimmunosuppression in attempts to treat rejection, such as use of excessive steroids, antilymphocyte preparations, are fraught with a high incidence of infectious complications and metabolic sequelae, such as diabetogenesis and ulcerogenesis. In addition, each component of the “cocktail”, has its inherent limitations. It stands to reason that a baseline immunosuppressive agent which allows for less incidence of rejection, and easier treatment of rejection, would decrease both graft and patient loss.

FK 506 is a recent addition to the armamentarium of immunosuppressive agents. FK 506 shares some pharmacologic similarities with CyA, such as bioavailability, lipophilicity, and hepatic metabolism.8 Both drugs bind to proteins having a peptidyl-prolyl cis-trans isomerase activity, although the binding proteins for CyA and FK 506 are unique.9 A wealth of animal data1–12 and human experience13–16 suggest that FK 506 is effective in both the prevention and treatment of rejection. FK 506 appears to not only decrease the absolute incidence of rejection episodes, and allows for marked reduction in steroid doses, but makes the treatment of rejection much simpler. Nevertheless, a delineation of the side effects of FK 506 therapy is important in the comparison of two effective immunosuppressive agents. FK 506 and CyA share some of the same side effects, although they differ significantly in other important aspects. The purpose of this study was to examine the adverse effects associated with FK 506 therapy.

Adverse reactions requiring treatment or adjustment of FK 506 doses can be categorized into four primary areas: (1) alterations in kidney function; (2) alterations in glucose metabolism; (3) neurotoxicity; and (4) susceptibility to infection or malignancy.