How do calcineurin inhibitors cause nephrotoxicity?

Acute CNI Nephrotoxicity: Acute calcineurin inhibitor induced nephrotoxicity is primarily due to acute arteriolopathy. The original finding of acute arteriole vasoconstriction caused by cyclosporine on the afferent arterioles was first discovered by Murray and colleagues and later confirmed by subsequent studies.

How does CNI cause nephrotoxicity?

Tubular Effects: “Toxic Tubulopathy.” Histologically, acute CNI nephrotoxicity has been associated with isometric vacuolization of the tubular cytoplasm, as a result of enlargement of the endoplasmic reticulum and increased lysosomes (80–84).

How does a calcineurin inhibitor work?

What are calcineurin inhibitors? Calcineurin inhibitors are drugs that work by inhibiting the calcium-dependent protein phosphatase calcineurin, an enzyme that results in activation of T lymphocytes through the upregulation of interleukin-2 and related cytokines, and leads to immunosuppression [1].

What is the mechanism of action of tacrolimus?

Tacrolimus bonds to an immunophilin, FK506 binding protein (FKBP). This complex inhibits calcineurin phosphatase. The drug inhibits calcium-dependent events, such as interleukin-2 gene transcription, nitric oxide synthase activation, cell degranulation, and apoptosis.

What drugs are calcineurin inhibitors?

Calcineurin inhibitors (CNI) are composed of three drugs (cyclosporine, tacrolimus, and pimecrolimus). They are primarily used as immunosuppressive drugs, and inhibit the key signaling phosphatase calcineurin, thus called calcineurin inhibitors.

Is CNI nephrotoxicity reversible?

CNI nephrotoxicity is manifested either as acute kidney injury (AKI), which is largely reversible after reducing the dose, or as chronic progressive renal disease, which is usually irreversible [2-5].

When do you use calcineurin inhibitors?

Because calcineurin inhibitors suppress the immune system they are known as immunosuppressants. Topical calcineurin inhibitors (pimecrolimus, tacrolimus) may be used to treat inflammatory skin conditions such as atopic dermatitis when other treatments have failed.

What do calcineurin inhibitors treat?

Topical calcineurin inhibitors (TCIs) work by altering the immune system and have been developed for treating atopic eczema. There are two types available: tacrolimus ointment (Protopic) for moderate to severe eczema and pimecrolimus cream (Elidel) for mild to moderate eczema. ‘Topical’ means applied to the skin.

What is the function of tacrolimus?

Tacrolimus is used with other medications to prevent rejection of a kidney, heart, or liver transplant. This medication belongs to a class of drugs known as immunosuppressants. It works by weakening your body’s defense system (immune system) to help your body accept the new organ as if it were your own.

Which drug is a calcineurin?

Calcineurin inhibitors (CNI) are a family of three drugs (cyclosporine, tacrolimus, and pimecrolimus) that clinicians can use to suppress the immune system.

Can tacrolimus damage kidneys?

Tacrolimus works by suppressing the immune system to prevent the white blood cells from trying to get rid of the transplanted organ. Tacrolimus is a very strong medicine. It can cause side effects that can be very serious, such as kidney problems. It may also decrease the body’s ability to fight infections.

What are examples of topical calcineurin inhibitors?

There are two types of topical calcineurin inhibitors called tacrolimus ointment (Protopic 0.03% and 0.1%) and pimecrolimus cream (Elidel). They are classified as immunomodulating agents. This means that they act on the immune system to reduce skin inflammation.

What kind of nephrotoxicity does calcineurin inhibitor cause?

Schematic representation of the etiology of calcineurin inhibitor nephrotoxicity. CNI, calcineurin inhibitor; TMA, thrombotic microangiopathy; EMT, epithelial mesenchymal transition; ECM, extracellular matrix; GFR, glomerular filtration rate; FSFS, focal segmental glomerulosclerosis; ROS, reactive oxygen species. *Only in native kidneys. Table 1.

What happens to renin secretion during calcineurin inhibition?

The increased renin secretion associated with calcineurin inhibition is sometimes seen as hyperplasia of the juxtaglomerular apparatus, which is typically observed in states of chronic renin stimulation ( 54 ).

How are calcineurin inhibitors related to CYP3A4?

Calcineurin inhibitors are substrates of P-glycoprotein and CYP3A4. Drugs that inhibit or compete as substrates for these enzymes can increase absorption and reduce metabolism of calcineurin inhibitors, causing increased serum concentrations and adverse effects.

How are calcineurin inhibitors used in organ transplantation?

Calcineurin inhibitors are widely used in the management of autoimmune disorders and have revolutionized organ transplantation. These agents block T-cell proliferation by inhibiting the Ca++ -calmodulin–sensitive phosphatase, calcineurin. Unfortunately, these drugs have been shown to cause high-turnover bone loss in both human and animal studies.