EXPLANATION


Tacrolimus, also known as Prograf, FK506, or TAC, is a macrolide that is commonly utilized for the maintenance of immunosuppression in heart transplant recipients. The immunosuppressive properties of tacrolimus stem from its selective inhibition of calcineurin, which leads to decreased proliferation of T-lymphocytes and decreased production of interleukin 2 (IL-2), interleukin 3 (IL-3), interleukin 4 (IL-4), interferon gamma, CD40L, GM-CSF, and tumor necrosis factor alpha (TNF-alpha). It is a lipophilic medication that is predominantly metabolized by cytochrome P-450 CYP3A enzymes in the liver. Tacrolimus is eliminated via biliary excretion. The elimination half-life is dependent on the formulation (immediate-release versus extended-release).


Tacrolimus is known to be nephrotoxic. Renal injury is more likely with higher doses of the medication, liver disease, inhibition of cytochrome P-450 CYP3A (notably by grapefruit) leading to higher plasma levels of the medication and its active metabolites, pre-existing renal disease, and the concomitant use of other nephrotoxic agents such as non-steroidal anti-inflammatory drugs. The nephrotoxic effects can lead to either acute kidney injury, which can often be reversed with a reduction in the dose of the drug, or chronic progressive kidney disease, which may be irreversible and lead to end-stage renal disease.


The mechanism of tacrolimus nephrotoxicity is not entirely known but is believed to be similar to cyclosporine, another calcineurin inhibitor, with a longer history of use clinically and known nephrotoxic properties. The acute nephrotoxic effects of both medications are thought to be due to endothelial cell dysfunction in afferent and efferent glomerular arterioles, leading to vasoconstriction that limits renal blood flow and glomerular filtration. Pathological examination of renal tissue in patients with chronic progressive renal disease has demonstrated arteriopathy, tubular damage, glomerular damage, and interstitial fibrosis. These findings may be responsible for or worsen associated pathologic states, such as hypertension, that may then compound existing renal disease. Thrombotic microangiopathy is an additional mechanism by which tacrolimus may cause renal injury.


The primary approach to minimizing tacrolimus-associated nephrotoxicity is by limiting exposure to the medication. This can be accomplished with dose reduction, the addition of adjunctive immunosuppressive medications such as mycophenolate mofetil, avoidance of medications and substances that inhibit tacrolimus metabolism in the liver, avoidance of additional nephrotoxic agents and the management of physiologic states that may worsen renal disease such as hypertension.


Other important side effects of tacrolimus include metabolic disturbances, such as hyperkalemia, hypophosphatemia, hypomagnesemia, metabolic acidosis secondary to reduced renal acid excretion, hypercalciuria, neurotoxicity (headaches, tremors, neuropathy, encephalopathy, seizures, posterior reversible encephalopathy syndrome), glucose intolerance, hyperuricemia, and gout. There is a published case report of bronchiolitis obliterans, which the authors believed was caused by tacrolimus in a 19-month-old heart transplant recipient.


Mycophenolate mofetil (MMF, CellCept, Myfortic), like its predecessor azathioprine, is an anti-metabolite medication that acts as a reversible, non-competitive inhibitor of inosine monophosphate dehydrogenase, thus inhibiting the synthesis of GMP and T cell and B cell function. Mycophenolate mofetil is used to decrease the dose of calcineurin inhibitors and, thereby, calcineurin inhibitor toxicity. The main adverse effects of MMF are hematologic (leukopenia, anemia, and thrombocytopenia) and gastrointestinal (diarrhea and vomiting).


Prednisone is a synthetic glucocorticoid pro-drug that is metabolized in the liver to prednisolone. Prednisone is utilized as an immunosuppressant medication and an anti-inflammatory medication. Although there are many undesirable side effects of glucocorticoid therapy, prednisone is not strongly associated with nephrotoxicity.


The correct answer is B. Renal toxicity is a major risk factor associated with the use of calcineurin inhibitor-type medications tacrolimus and cyclosporin. MMF and steroids are generally not associated with renal injury.


REFERENCES


Hardinger K, Magee CC. Pharmacology of calcineurin inhibitors. In UpToDate, Connor RF (Ed), Wolters Kluwer. https://www.uptodate.com/contents/pharmacology-of-calcineurin-inhibitors Accessed on October 2, 2024.


Hardinger K, Brennan DC, Lam AQ. Cyclosporine and tacrolimus nephrotoxicity. In UpToDate, Connor RF (Ed), Wolters Kluwer. https://www.uptodate.com/contents/cyclosporine-and-tacrolimus-nephrotoxicity Accessed on October 3, 2024.


Kirpalani A, Teoh CW, Ng VL, Dipchand AI, Matsuda-Abedini M. Kidney disease in children with heart or liver transplant. Pediatr Nephrol. 2021;36(11):3595-3605. doi:10.1007/s00467-021-04949-5


Karim F, Misra A, Sehgal S. Bronchiolitis obliterans organising pneumonia secondary to tacrolimus toxicity in a pediatric cardiac transplant recipient. Cardiol Young. 2023;33(4):630-632. doi:10.1017/S1047951122002049


Crowley KL, Webber S. Immunosuppressive agents in pediatric heart transplantation. In: Munoz R, da Cruz EM, Vetterly CG, Cooper DS, Berry D, Eds. Handbook of Pediatric Cardiovascular Drugs. 2nd Edition. London, UK: Springer-Verlag; 2014: pp 329-363.