What are the effects of calcineurin (Calcineurin Phosphatase) toxicity?

From the Guidelines

Calcineurin inhibitor toxicity is a significant concern when using medications like tacrolimus and cyclosporine, and can cause both acute and chronic toxicity affecting multiple organ systems, including nephrotoxicity, neurotoxicity, and metabolic complications, as noted in the 2021 KDIGO guideline for the management of glomerular diseases 1. The most concerning toxicities include:

• Nephrotoxicity (causing acute kidney injury or chronic kidney disease)
• Neurotoxicity (presenting as tremors, headaches, seizures, or posterior reversible encephalopathy syndrome)
• Metabolic complications (hypertension, hyperglycemia, hyperlipidemia) Management involves therapeutic drug monitoring to maintain levels within a narrow therapeutic window, with target trough levels typically 5-10 ng/mL for tacrolimus and 100-200 ng/mL for cyclosporine, though these targets vary by indication and time post-transplant, as discussed in the 2013 KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis 1. Dose reduction is the primary intervention for toxicity, but in severe cases, switching to alternative immunosuppressants like mTOR inhibitors (sirolimus, everolimus) or belatacept may be necessary, as recommended in the 2007 workshop on cyclosporin in idiopathic glomerular disease associated with the nephrotic syndrome 1. Prevention strategies include:
• Avoiding nephrotoxic drug combinations
• Maintaining adequate hydration
• Monitoring renal function regularly, with monthly serum creatinine levels and yearly glomerular filtration rates in patients who are maintained on therapy for greater than 1 year, as suggested in the 2009 guidelines of care for the management of psoriasis and psoriatic arthritis 1. Calcineurin inhibitor toxicity occurs because these drugs inhibit calcineurin phosphatase activity, which not only suppresses T-cell activation but also affects cellular functions in non-immune cells, particularly in the kidneys where they cause vasoconstriction of the afferent arteriole and direct tubular damage.

From the Research

Effects of Calcineurin Toxicity

The effects of calcineurin toxicity, particularly in the context of calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus, are multifaceted and can lead to significant adverse effects, especially nephrotoxicity. Key points regarding these effects include:

• Nephrotoxicity is a major concern with the use of CNIs, affecting the long-term outcome and survival of transplant patients 2, 3, 4, 5, 6.
• The nephrotoxic effects of CNIs can manifest as both acute and chronic damage to the kidneys, including glomerular sclerosis, tubular atrophy, and interstitial fibrosis 3, 4, 6.
• Chronic nephrotoxicity is associated with prolonged use of CNIs and can lead to end-stage renal failure 3, 6.
• The development of nephrotoxicity is related to both reversible alterations and irreversible damage to all compartments of the kidneys 3.
• Local exposure to CNIs, rather than systemic exposure, may play a more significant role in the development of nephrotoxicity 3.
• Other factors, such as genetic polymorphisms, older kidney age, salt depletion, and the use of nonsteroidal anti-inflammatory drugs, can increase susceptibility to CNI nephrotoxicity 3, 6.
• Different CNIs may have varying levels of toxicity, with cyclosporine potentially causing greater renal damage than tacrolimus 5.
• The mechanisms underlying CNI nephrotoxicity involve the inhibition of calcineurin, leading to endoplasmic reticulum stress and unfolded protein response in renal tubular cells 5.

Comparison of Calcineurin Inhibitors

Comparing the effects of different calcineurin inhibitors:

• Tacrolimus-based therapy appears to be superior to cyclosporine in terms of reduced early CNI nephrotoxicity and fewer rejection episodes, but both have comparable chronic arteriolar toxicity 4.
• Cyclosporine A induces proapoptotic endoplasmic reticulum stress in renal tubular cells to a greater extent than tacrolimus 5.

Management and Prevention

Strategies for managing and preventing CNI nephrotoxicity include:

• Early recognition of indicators of patient and graft dysfunction 2.
• The use of CNI-sparing regimens or withdrawal of CNIs where possible 2.
• The introduction of new immunosuppressive agents that may offer improved efficacy with reduced toxicity 2.
• Pharmacological modulation of the unfolded protein response to alleviate renal side effects of CNIs 5.