Trimethoprim and acute kidney injury (AKI)

• hyperkalaemia has been demonstrated to occur with the administration of both high and standard dosages of trimethoprim
  
  
• trimethoprim reduces renal potassium excretion through the competitive inhibition of epithelial sodium channels in the distal nephron, in a manner identical to the potassium-sparing diuretic amiloride
  
  
• increased risk for hyperkalaemia with trimethoprim treatment appears to be related to both higher dosages and underlying renal impairment
  • probable that other disturbances in potassium homeostasis, such as hyopoaldosteronism and treatment with medications that impair renal potassium excretion, are also risk factors for hyperkalaemia with trimethoprim therapy
    
    
• prevention of this adverse reaction depends upon recognition of patients at risk of developing hyperkalaemia as well as proper dosage selection of trimethoprim for the patient's prevailing glomerular filtration rate
  
  
• management of hyperkalaemia often mandates discontinuation of the drug, volume repletion with isotonic fluids, and other therapies specific to hyperkalaemia
  • in circumstances where continued treatment with trimethoprim is required, induction of high urinary flow rates with intravenous fluids and a loop diuretic, as well as alkalinisation of the urine, have been shown to block the antikaliuretic effect of trimethoprim on distal nephron cells

Hyperkalaemia and non-oliguric renal failure has been associated with trimethoprim use (1,2,3).

Notes:

• renal failure has been reported with trimethoprim in combination with sulphamethoxazole (cotrimoxazole)
  • trimethoprim can also reversibly increase serum creatinine concentration and reduce creatinine clearance without decreasing glomerular filtration rate both in people with normal renal function and in those with renal allografts
  • trimethoprim alone can cause an important but reversible increase in serum creatinine concentration in acute uncomplicated cystitis and in chronic renal failure
• a cohort study highlighted the association of prescription of trimethoprim with hyperkalaemia and AKI (acute kidney inury), but not with death, in older adults being treated for a simple UTI (3)
  • the authors have contextulised the results
    • while the odds of hyperkalaemia and AKI with trimethoprim prescription are increased by 127% and 72%, respectively, compared with amoxicillin prescription, the increase in the absolute risk is small
    • the authors state that for 1,000 UTI episodes treated with trimethoprim rather than amoxicillin, there would be one additional case of hyperkalaemia and two of AKI
      • the authors state that "the relative risk increase is similar across population groups, but the higher baseline risk among those taking renin-angiotensin system blockers and potassium-sparing diuretics translates into higher absolute risks of acute kidney injury and hyperkalaemia in these groups...", ie implying that trimethoprim should be used with particular caution in patients taking renin-angiotensin system blockers or potassium-sparing diuretics

Reference:

• 1) Perazella MA. Trimethoprim-induced hyperkalaemia: clinical data, mechanism, prevention and management. .Drug Saf. 2000 Mar;22(3):227-36.
• 2) Smith GW, Cohen SB.Hyperkalaemia and non-oliguric renal failure associated with trimethoprim.BMJ. 1994 Feb 12;308(6926):454.
• 3) Crellin E , Mansfield KE , Leyrat C , et al . Trimethoprim use for urinary tract infection and risk of adverse outcomes in older patients: cohort study. BMJ 2018;360:k341