Old and New Calcineurin Inhibitors in Lupus Nephritis

Abstract

Calcineurin inhibitors (CNIs) are drugs that inhibit calcineurin, a key phosphatase that dephosphorylates a transcription factor called the nuclear factor of activated T cells (NFAT), allowing its translocation into the nucleus of quiescent T cells. In the nucleus, NFAT activates interleukin 2, which stimulates the proliferation and differentiation of T-cells. CNIs can also stabilize the actin cytoskeleton of podocytes reducing proteinuria. Thanks to these characteristics, CNIs have been often used in the treatment of autoimmune diseases. However, the therapeutic index of CNIs is narrow, and their interactions with other drugs can increase toxicity or reduce efficacy. In lupus nephritis, cyclosporine and tacrolimus have been used both in induction and maintenance therapies. Observational studies and randomized controlled trials showed that both cyclosporine and tacrolimus can increase efficacy. Tolerance is satisfactory if low doses are used and the patient is carefully monitored. More recently, a new CNI, called voclosporin (VCS), has been approved by the Food and Drug Administration for use in lupus nephritis. VCS offers potential advantages over other CNIs. In two large multiethnic trials, VCS was not associated with adverse renal and metabolic events and obtained positive results despite a novel and rapid corticosteroid tapering regime.

Synthetic Pharmacotherapy for Systemic Lupus Erythematosus: Potential Mechanisms of Action, Efficacy, and Safety

“…Inhibition of calcineurin prevents the translocation of cytokine-related transcription factors (such as those responsive to IL-2), with subsequent inactivation of T cells achieving modulation of autoimmune activity [ 255 ]. In addition, cyclosporine has been shown to have effects on podocytes that may reduce proteinuria [ 250 , 254 , 256 ].…”

“…It is metabolized mainly through CYP3A4 and is a substrate of P-glycoprotein. Its pharmacokinetics can be altered by food intake or even in situations such as hypoalbuminemia or hepatic failure [ 254 , 256 ].…”

Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders

“…The first drug to target a phosphatase to be FDA approved was the calcineurin inhibitor cyclosporine 15 . Since the initial approval of cyclosporine in 1983 for immunosuppression following organ transplantation, additional cyclosporine formulations and the calcineurin inhibitors tacrolimus/FK506, pimecrolimus and voclosporin have been approved for the prevention of organ transplant rejection and as immunosuppressants in rheumatoid arthritis (RA), lupus nephritis, psoriasis, atopic dermatitis, keratoconjunctivitis sicca and more 15 , 16 . Another drug, fingolimod/FTY720, indirectly activates protein phosphatase 2A (PP2A) by binding to its negative regulator su(var)3-9, enhancer of zeste, trithorax (SET) and was FDA approved for the treatment of multiple sclerosis (MS) in 2010 (refs.…”

“…Another drug, fingolimod/FTY720, indirectly activates protein phosphatase 2A (PP2A) by binding to its negative regulator su(var)3-9, enhancer of zeste, trithorax (SET) and was FDA approved for the treatment of multiple sclerosis (MS) in 2010 (refs. 15 , 16 ). However, further introduction of phosphatase-modulating agents into the clinic was severely hampered by historic difficulties in targeting these enzymes 17 .…”

Non-Immunologic Causes of Late Death-Censored Kidney Graft Failure: A Personalized Approach

“…Studies show that blood levels do not reflect the intracellular concentration of CNI and may be misleading [ 45 ]. In addition, one should take into account the impact of concurrent drugs that can interfere with CYP450 or P glycoprotein, thus modifying the blood levels [ 46 ]. An expert consensus pointed out that acute rejection and kidney toxicity still occur in patients showing blood CNI concentrations within the therapeutic range [ 47 ].…”