Does trimethoprim (TMP) cause Acute Kidney Injury (AKI)?

From the Guidelines

Trimethoprim can cause acute kidney injury (AKI), particularly in high-risk patients, and its use should be avoided or closely monitored in patients with pre-existing kidney disease or those at risk of nephrotoxicity. This antibiotic works by inhibiting creatinine secretion in the proximal tubule, which can lead to a rise in serum creatinine levels without actual kidney damage, as noted in the context of managing nephrotoxins during acute kidney disease and renal recovery 1. However, trimethoprim can also cause genuine AKI through several mechanisms, including acute interstitial nephritis, crystal nephropathy, and hyperkalemia.

Risk factors for trimethoprim-induced AKI include:

• Older age
• Pre-existing kidney disease
• Dehydration
• Concurrent use of other nephrotoxic medications The risk is dose-dependent and increases with higher doses and longer treatment durations. For patients at high risk, alternative antibiotics should be considered when appropriate, as suggested by the consensus statement on avoiding nephrotoxic medications in patients with acute kidney disease 1.

If trimethoprim must be used in high-risk patients, kidney function should be monitored closely, adequate hydration maintained, and the lowest effective dose prescribed for the shortest necessary duration. Most cases of trimethoprim-induced AKI are reversible with prompt discontinuation of the medication, though recovery may take days to weeks. It's also important to consider the recommendations provided in package inserts or guidelines specific to a drug or drug class, such as avoiding combination trimethoprim and sulfamethoxazole treatment if creatinine clearance is <15 ml/min, as mentioned in the context of managing nephrotoxins during acute kidney disease 1.

From the FDA Drug Label

Sulfamethoxazole and trimethoprim should be given with caution to patients with impaired renal or hepatic function Urinalyses with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function. The trimethoprim component of sulfamethoxazole and trimethoprim may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency

Key Points:

• Trimethoprim may cause hyperkalemia in patients with renal insufficiency.
• Patients with impaired renal function should be given sulfamethoxazole and trimethoprim with caution.
• Renal function tests should be performed during therapy, especially in patients with impaired renal function.

The FDA drug label suggests that trimethoprim may cause acute kidney injury (AKI) indirectly by causing hyperkalemia in patients with underlying renal insufficiency 2 2.

From the Research

Trimethoprim and Acute Kidney Injury (AKI)

• Trimethoprim, often used in combination with sulfamethoxazole, has been associated with an increased risk of acute kidney injury (AKI) in various studies 3, 4, 5, 6, 7.
• The mechanism of trimethoprim-induced AKI is thought to be related to intrinsic renal impairment rather than interstitial nephritis or competition for creatinine clearance 3.
• Risk factors for trimethoprim-associated AKI include:
  • Hypertension 3, 4
  • Diabetes mellitus 3
  • Low body mass index (BMI) 4
  • High-dose trimethoprim/sulfamethoxazole 4
  • Concomitant use of loop diuretics 4
  • Concurrent use of vancomycin 5
  • Elevated baseline serum creatinine level 5
• The incidence of AKI associated with trimethoprim/sulfamethoxazole use has been reported to be around 11-21% in different studies 3, 4, 5.
• In most cases, AKI resolves promptly after discontinuation of trimethoprim/sulfamethoxazole therapy 3, 7.
• It is essential to monitor renal function in patients at high risk of AKI, especially those with pre-existing renal impairment or other risk factors 4, 6.