Preventing Aminoglycoside-induced AKI

The IRIS Board (updated 2022)

Dogs appear to be more sensitive than cats to gentamicin-induced nephrotoxicity which may be lethal. As other aminoglycosides are not authorised for use in dogs or cats, the precise susceptibility of the dog and cat to acute kidney injury (AKI) following their use is not established. In the absence of such information it is wise to follow the same precautions as detailed for gentamicin. Prevention and follow-up are very important.

A - Prior to aminoglycoside treatment:

1. Consider carefully the potential risk factors: dehydration, concomitant treatment with furosemide, use of other nephrotoxic drugs, systolic hypotension, hypokalemia, previous history of AKI, pre-existing chronic kidney disease (CKD). When such factors are identified, alternatives to aminoglycoside-treatment should be considered.
2. Perform urinalysis (measure urine specific gravity, examine for glycosuria, proteinuria [measure urine protein/creatinine ratio (UPC)], abnormal sediment). If abnormalities are detected, investigate carefully to determine the underlying cause before deciding whether to prescribe aminoglycosides.
3. Blood tests: determine blood creatinine concentration, referring to IRIS guidelines for CKD. Avoid using aminoglycosides if the blood creatinine concentration is suggestive of Stage 2 or above, unless antibiotic therapy is essential for a life-threatening condition and there are no alternatives to aminoglycosides.
4. In borderline cases (serum creatinine approaching Stage 2 cut-off, pre-existing proteinuria, or renal tubular dysfunction (glucosuria)), further investigations might be considered to evaluate renal risk:
   1. Imaging: abdominal radiograph and/or ultrasonographic examination.
   2. Measurement of blood pressure (High risk hypertension: systolic > 180 mm/Hg is indicative of renal damage and risk).
   3. Urine culture to evaluate for occult pyelonephritis. Other infectious disease testing may be indicated based geographic region and endemic infectious agents.

B - Select the appropriate dosage and duration of treatment:

Some of the treatment recommendations are not authorised for use in all geographical regions and some may not be authorised for use in dogs and/or cats. Such suggested dose rates are therefore empirical. It is the treating veterinarian's duty to make a risk:benefit assessment for each patient prior to administering any treatment.

Dosage of most commonly used aminoglycosides in dogs and cats (single dose administered IV, IM or SC once every 24 hours)*

**From Plumb's Veterinary Drug Handbook, 9th Edition. Wiley. St. Louis, MO. 2018

Risk of nephrotoxicity increases with the duration of the treatment as aminoglycoside nephrotoxicity is cumulative. Giving the total daily dose in one administration lowers the risk of toxicity as it reduces the proportion of the total daily dose that can accumulate within the kidney.

Azotemic patients (IRIS CKD stages 2-4) who do not have an alternative antimicrobial that can be administered require modification of the dosing interval to prevent drug accumulation. Aminoglycoside antibiotics undergo renal elimination, therefore the half-life will be prolonged in dogs with substantially reduced kidney function leading to unintended drug exposure. Pharmacokinetic studies have not been performed in azotemic dogs and cats to determine appropriate modifications to dosing. Extrapolating from human guidelines, patients with stage 2 and 3 CKD should have the frequency of administration reduced to once every 48 hours. Patients with stage 4 CKD should have the frequency of administration reduced to once every 72 hours. Therapeutic drug monitoring of peak and trough plasma concentrations (see below) should be performed when dose modification is performed to avoid drug accumulation

Duration of therapy is dependent on disease process that is being treated. Veterinarians should review available consensus guidelines on appropriate duration of therapy based upon site and severity of infection. Extending treatment beyond what is needed may increase the risk of nephrotoxicity.

C - During the treatment:

1. Assess the hydration status of the patient (body weight, total plasma protein concentration and haematocrit) and ensure adequate hydration is maintained during treatment.
2. If therapeutic drug monitoring is available, ensure the plasma concentration of gentamicin has decreased to below 1 mg/l (1 µ/ml) before the next dose is administered.
3. Assess serum creatinine concentration every 1-2 days during treatment. Small changes (i.e., 0.3 mg/dl, or 25 μmol/L) in blood creatinine concentration or decrease in urine production should be regarded as significant and promote reassessment of the treatment (refer to IRIS guidelines for grading AKI).
4. Re-assess carefully the pre-treatment variables indicated in section A, points 2 and 3.
5. Repeat these assessments every 1-2 days to detect any change. If in doubt re renal damage, determine urine GGT / creatinine ratio (when available in the laboratory): an increase is an early indicator of nephrotoxicity. Novel kidney injury markers, such as urine neutrophil gelatinase-associated lipocalin (N-GAL), clusterin, albumin, trefoil factor-3 (TFF-3), and N-acetyl-β-D-glucosaminidase (NAG) detect kidney injury earlier than changes in serum creatinine; however their utility is limited by lack of veterinary diagnostic laboratories offering these assays.
6. Continue monitoring for one week after discontinuing the treatment as AKI may occur later (aminoglycosides accumulate inside proximal tubular cells and persist for long periods after dosing).

D - If findings suggest development of AKI (urine: renal casts in sediment, glycosuria, low specific gravity; blood: azotemia):

1. Stop aminoglycoside administration.
2. Hospitalize the patient and monitor urine production. Non-oliguric AKI occurs generally and is reversible, whereas oliguric AKI has a poor prognosis.
3. Start adequate intravenous fluid therapy to restore perfusion to the kidneys and to correct hypovolemia and dehydration.
4. Monitor: urea, creatinine and electrolytes daily during hospitalization. Electrolytes may require more frequent assessment if abnormalities (hypokalemia or hyperkalemia, etc.) are present. Treat electrolyte disturbances accordingly.
5. If AKI is worsening, consider renal replacement therapy (hemodialysis, hemofiltration, or peritoneal dialysis).
6. After apparent recovery from aminoglycoside-induced AKI, some renal impairment is likely to remain. Patients should be monitored periodically throughout the first year following AKI to evaluate for further changes to kidney function.