Can supratherapeutic levels of tacrolimus (immunosuppressive medication) cause Acute Kidney Injury (AKI)?

From the Guidelines

Yes, supratherapeutic levels of tacrolimus can cause acute kidney injury (AKI). Tacrolimus, an immunosuppressant medication commonly used after organ transplantation, has a narrow therapeutic window, with target blood levels typically ranging from 5-15 ng/mL depending on the transplant type and time since transplantation [ 1 ]. When tacrolimus levels exceed the therapeutic range, nephrotoxicity is a significant concern.

Key Points

• Tacrolimus causes vasoconstriction of the afferent arteriole in the kidney, reducing renal blood flow and glomerular filtration rate [ 1 ].
• This vasoconstriction is dose-dependent, meaning higher tacrolimus levels increase the risk and severity of kidney injury.
• Additionally, tacrolimus can cause tubular damage through direct toxicity to renal tubular cells.
• Patients with supratherapeutic tacrolimus levels may present with rising creatinine, decreased urine output, electrolyte abnormalities, and fluid retention.
• Management typically involves dose reduction or temporary discontinuation of tacrolimus, with close monitoring of drug levels and kidney function.
• Risk factors for tacrolimus-induced AKI include dehydration, concurrent use of other nephrotoxic medications, and drug interactions that increase tacrolimus levels.

Recommendations

• Tacrolimus trough levels should be kept at 6-10 ng/ml during the first month followed by 4-8 ng/ml thereafter [ 1 ].
• It is recommended to combine tacrolimus with other immunosuppressive drugs to allow for a lower range of tacrolimus trough levels and to help preserve renal function [ 1 ].
• The administration of basiliximab induction with delayed introduction of tacrolimus is strongly recommended in patients at risk of developing post-transplant renal dysfunction [ 1 ].

From the FDA Drug Label

Tacrolimus, like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration

Yes, supratherapeutic levels of tacrolimus can cause acute kidney injury due to its nephrotoxic effects, which can be reversible by reducing the dosage or temporarily interrupting tacrolimus administration 2.

From the Research

Association between Supratherapeutic Tacrolimus Levels and Acute Kidney Injury

• Supratherapeutic levels of tacrolimus have been associated with an increased risk of acute kidney injury (AKI) in various studies 3, 4, 5, 6.
• A retrospective observational cohort study of heart transplantation patients found that supratherapeutic whole-blood tacrolimus trough concentrations were independently associated with AKI (OR 1.66; 95% CI 1.20-2.31) 3.
• Another study of lung transplantation patients found that supra-therapeutic tacrolimus concentrations were related to the early onset of AKI (OR 1.55; 95% CI 1.06-2.27) 4.
• A clinical and histological analysis of acute tacrolimus nephrotoxicity in renal allografts found that high trough levels of whole blood tacrolimus and the existence of moderate-to-severe arteriosclerosis in allograft arteries have the potential to cause tacrolimus nephrotoxicities 5.

Risk Factors for Tacrolimus-Induced Acute Nephrotoxicity

• High trough concentrations of tacrolimus have been identified as a risk factor for acute nephrotoxicity in children with nephrotic syndrome (OR, 1.48; 95% CI, 1.16 to 1.88; P < 0.001) 6.
• Diarrhea has also been found to potentiate the risk of tacrolimus-induced acute nephrotoxicity in children with nephrotic syndrome (OR, 22.00; 95% CI, 1.58 to 306.92; P = 0.022) 6.
• The use of certain medications, such as ranolazine, in combination with tacrolimus and diltiazem, may also increase the risk of tacrolimus toxicity and reversible acute kidney injury 7.

Clinical Characteristics of Tacrolimus-Induced Acute Nephrotoxicity

• Tacrolimus-induced nephrotoxicity can present with a range of clinical characteristics, including fatigue, loss of appetite, tremors, and decreased urine output 7.
• The onset of nephrotoxicity can occur within days to weeks after initiation of tacrolimus therapy, and the severity of the condition can vary from mild to severe 5, 6.
• Recovery from nephrotoxicity is possible with reduction or discontinuation of tacrolimus therapy, and close monitoring of tacrolimus levels is essential to prevent and manage this condition 3, 4, 7, 6.