Preventing Aminoglycoside-Induced AKI

Guidance from the IRIS Board, updated 2022.

Dogs appear to be more sensitive than cats to gentamicin-induced kidney damage, which can be fatal. Because other aminoglycosides are not authorized for use in dogs or cats, the precise susceptibility of dogs and cats to acute kidney injury (AKI) after their use has not been established. In the absence of that information, it is wise to follow the same precautions as for gentamicin. Prevention and follow-up are very important.

A. Before Aminoglycoside Treatment

  1. Consider the risk factors carefully: dehydration, concurrent treatment with furosemide, use of other drugs that can damage the kidneys, low systolic blood pressure, low blood potassium, a previous episode of AKI, and pre-existing chronic kidney disease (CKD). When any of these risk factors is present, alternatives to aminoglycoside treatment should be considered.
  2. Perform a urinalysis: measure urine specific gravity, and check for glucose in the urine, proteinuria (by measuring the urine protein-to-creatinine ratio, or UPC), and abnormal sediment. If abnormalities are found, investigate carefully to determine the underlying cause before deciding whether to prescribe an aminoglycoside.
  3. Perform blood tests: measure blood creatinine concentration and interpret it using the IRIS guidelines for staging CKD. Avoid aminoglycosides if blood creatinine suggests IRIS CKD Stage 2 or above, unless antibiotic therapy is essential for a life-threatening condition and there is no alternative to an aminoglycoside.

In borderline cases, such as a creatinine approaching the Stage 2 cut-off, pre-existing proteinuria, or evidence of renal tubular dysfunction such as glucose in the urine with normal blood glucose, further tests may be considered to evaluate the risk to the kidneys, for example symmetric dimethylarginine (SDMA) or a direct measurement of glomerular filtration rate.

B. Select the Appropriate Dosage and Duration of Treatment

Some of the treatment recommendations are not authorized in all geographical regions, and some may not be authorized for use in dogs or cats. The suggested dose rates are therefore empirical. It is the treating veterinarian's duty to make a risk-benefit assessment for each patient before giving any treatment.

Doses of the most commonly used aminoglycosides in dogs and cats, each given as a single dose intravenously, intramuscularly, or subcutaneously once every 24 hours, from Plumb's Veterinary Drug Handbook, 9th edition (Wiley, 2018):

  • Amikacin: dogs 15 to 30 mg/kg once daily; cats 10 to 15 mg/kg once daily
  • Gentamicin: dogs 9 to 15 mg/kg once daily; cats 5 to 8 mg/kg once daily
  • Tobramycin: dogs 9 to 14 mg/kg once daily; cats 5 to 8 mg/kg once daily

The risk of kidney damage increases with the duration of treatment, because aminoglycoside nephrotoxicity is cumulative. Giving the total daily dose as a single administration lowers the risk of toxicity, because it reduces the proportion of the daily dose that can accumulate within the kidney.

Azotemic patients (IRIS CKD Stages 2 to 4) for whom no alternative antimicrobial is available need a longer dosing interval to prevent the drug from accumulating. Aminoglycosides are eliminated by the kidneys, so their half-life is prolonged in animals with substantially reduced kidney function, leading to unintended drug exposure. Pharmacokinetic studies have not been performed in azotemic dogs and cats to determine appropriate dose modifications. Extrapolating from human guidelines, patients with Stage 2 or Stage 3 CKD should have the dosing frequency reduced to once every 48 hours, and patients with Stage 4 CKD to once every 72 hours. Therapeutic drug monitoring of peak and trough plasma concentrations (see below) should be performed whenever the dose is modified, to avoid drug accumulation.

The duration of therapy depends on the disease being treated. Veterinarians should review the available consensus guidelines on appropriate treatment duration for the site and severity of the infection. Extending treatment beyond what is needed may increase the risk of nephrotoxicity.

C. During Treatment

  • Assess the patient's hydration status (body weight, total plasma protein concentration, and hematocrit), and make sure adequate hydration is maintained throughout treatment.
  • If therapeutic drug monitoring is available, make sure the plasma gentamicin concentration has fallen below 1 mg/L (1 µg/mL) before the next dose is given.
  • Measure serum creatinine every 1 to 2 days during treatment. Small changes in blood creatinine, such as an increase of 0.3 mg/dL (about 26 µmol/L), or a decrease in urine production, should be regarded as significant and should prompt a reassessment of treatment. Refer to the IRIS guidelines for grading AKI.
  • Carefully reassess the pre-treatment urinalysis and blood tests listed in section A, points 2 and 3, repeating them every 1 to 2 days to detect any change.
  • If kidney damage is suspected, measure the urine GGT-to-creatinine ratio where the laboratory offers it, because an increase is an early indicator of nephrotoxicity. Novel kidney injury markers, such as urine neutrophil gelatinase-associated lipocalin (NGAL), clusterin, albumin, trefoil factor 3 (TFF-3), and N-acetyl-β-D-glucosaminidase (NAG), detect kidney injury earlier than changes in serum creatinine, but few veterinary diagnostic laboratories currently offer these assays.
  • Continue monitoring for one week after stopping treatment, because AKI may develop later. Aminoglycosides accumulate inside proximal tubular cells and persist there for long periods after dosing.

D. If Findings Suggest AKI Is Developing

Signs that AKI may be developing include renal casts in the urine sediment, glucose in the urine, low urine specific gravity, and azotemia. If these findings appear:

  1. Stop the aminoglycoside.
  2. Hospitalize the patient and monitor urine production. Non-oliguric AKI is more common and is often reversible, whereas oliguric AKI carries a poor prognosis.
  3. Start appropriate intravenous fluid therapy to restore blood flow to the kidneys and to correct hypovolemia and dehydration.
  4. Monitor urea, creatinine, and electrolytes daily during hospitalization. Electrolytes may need to be checked more often if abnormalities such as low or high potassium are present. Treat electrolyte disturbances accordingly.
  5. If AKI is worsening, consider renal replacement therapy (hemodialysis, hemofiltration, or peritoneal dialysis).

After apparent recovery from aminoglycoside-induced AKI, some kidney impairment is likely to remain. Patients should be monitored periodically throughout the first year after AKI to check for further changes in kidney function.