Trimethoprim/sulfamethoxazole and increased Creatinine: Mechanism

The serum creatinine concentration (Cr) is typically used as a surrogate for renal function. Hence, when increased it is often a sign of acute kidney injury. However, there are circumstances in which an increase in serum creatinine may not reflect true renal pathology. Such is the case with Trimethoprim/sulfamethoxazole (Bactrim/ Septra).

In normal, healthy subjects, about 15% of the urinary creatinine is from proximal tubule secretion. 

Creatinine is an organic positively charged molecule (cation) and hence is secreted by the organic cation secretory transporters (OCTs) that can be inhibited/ occupied by other organic cations.

Trimethoprim/sulfamethoxazole (organic cation) can cause a self-limited and reversible increase in serum creatinine (30 to 50 micromol/L) without affecting true renal function by occupying those transporters and preventing proximal tubular secretion.  

NOTE: Trimethoprim/sulfamethoxazole contains sulfa moieties and can also acute interstitial nephritis (AIN).

REFERENCES

1. Berg KJ et al. Renal effects of trimethoprim in ciclosporin- and azathioprine-treated kidney-allografted patients. Nephron. 1989;53(3):218-22.
2. Berglund F, Killander J, Pompeius R. Effect of trimethoprim-sulfamethoxazole on the renal excretion of creatinine in man. J Urol. 1975 Dec;114(6):802-8.
3. Andreev E, Koopman M, Arisz L. A rise in plasma creatinine that is not a sign of renal failure: which drugs can be responsible?. J Intern Med. 1999 Sep;246(3):247-52.