From the Guidelines
Tacrolimus can cause nephrotoxicity, and its renal effects should be managed by maintaining trough levels below 4-7 ng/ml during the first month and 3-5 ng/ml thereafter, as well as considering renal sparing regimens with combination immunosuppressants like mycophenolate mofetil (MMF) or azathioprine (AZA). The renal effects of tacrolimus are a significant concern, as they can lead to acute and chronic nephrotoxicity, resulting in reduced renal function and potentially impacting patient morbidity, mortality, and quality of life 1.
Management Strategies
To mitigate these effects, several management strategies can be employed:
- Maintaining tacrolimus trough levels within the recommended range to minimize nephrotoxicity
- Using renal sparing regimens that combine tacrolimus with other immunosuppressants like MMF or AZA, which can help reduce the required tacrolimus dose and subsequent renal toxicity
- Delaying the introduction of tacrolimus by 5 days in patients at risk of post-transplant renal dysfunction, using basiliximab and MMF or AZA instead, as recommended by the EASL clinical practice guidelines 1
- Considering conversion to a calcineurin inhibitor (CNI)-free everolimus-based regimen beyond the first year after transplant, although the benefit of this strategy in improving renal function is uncertain
Monitoring and Adjustments
Regular monitoring of renal function through serum creatinine and estimated GFR is crucial, as well as close monitoring of tacrolimus trough levels to ensure they remain within the recommended range. Dose adjustments should be made promptly when nephrotoxicity is suspected, and additional approaches like maintaining adequate hydration and avoiding concurrent nephrotoxic medications should be considered. Hypertension and electrolyte disturbances should also be monitored and treated appropriately to minimize the risk of renal damage. In severe cases, temporary dose reduction or brief discontinuation of tacrolimus may be necessary, although this must be balanced against the risk of rejection 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. Nephrotoxicity was reported in clinical trials [see Adverse Reactions (6. 1)]. 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
The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors).
When tacrolimus is used concurrently with other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust doses of both tacrolimus and/or concomitant medications during concurrent use [see Drug Interactions (7.2)].
Renal Effects of Tacrolimus:
- Tacrolimus can cause nephrotoxicity, which may be acute or chronic, due to its effects on renal vasculature 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.
- The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with CYP3A inhibitors or nephrotoxic drugs.
Management of Renal Effects:
- Monitor renal function and tacrolimus blood concentrations.
- Consider dosage reduction or temporary interruption of tacrolimus administration in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range.
- Adjust doses of both tacrolimus and/or concomitant medications during concurrent use with other known nephrotoxic drugs 2.
From the Research
Renal Effects of Tacrolimus
The renal effects of tacrolimus, an immunosuppressant commonly used in solid organ transplantation, have been extensively studied. Key findings include:
- Tacrolimus nephrotoxicity can be nonreversible and lead to kidney graft loss 3
- Systemic levels of tacrolimus, local renal exposure to tacrolimus, and exposure to metabolites of tacrolimus contribute to its development 3
- Local susceptibility factors, such as the age of the kidney, local renal P-glycoprotein, and renin-angiotensin system activation, also play a role in tacrolimus nephrotoxicity 3
Management of Renal Effects
To manage the renal effects of tacrolimus, several strategies can be employed:
- Monitoring of tacrolimus levels to avoid underexposure, which increases the risk of rejection, and overexposure, which increases the risk of adverse effects 3
- Adjustment of tacrolimus dose based on individual patient factors, such as renal function and genetic variability 4, 5, 6
- Use of alternative immunosuppressants, such as mycophenolate mofetil, in combination with tacrolimus to minimize nephrotoxicity 4, 6
- Consideration of genetic variability in genes involved in tacrolimus disposition and effect, such as CYP3A5, to predict risk of nephrotoxicity 7
Factors Associated with Renal Function
Several factors have been associated with renal function in patients taking tacrolimus, including:
- Tacrolimus trough level, with lower levels associated with better renal function 4, 6
- Mycophenolate mofetil dose, with higher doses associated with better renal function 4
- Donor age, acute rejection, and delayed graft function, which can all impact renal function 4
- Genetic variability in genes involved in tacrolimus disposition and effect, such as CYP3A5 and ABCB1 7