6. kidney toxicants - ethylene glycol, NSAIDs, grapes/raisins, vitamin D

bloodwork/urinalysis tests of renal function

• bloodwork

  • creatinine

  • blood urea nitrogen (BUN)

  • SDMA

• urinalysis

  • proteinuria

  • glucosuria

  • specific gravity

  • pH

  • urinary sediments: casts, crystals

what are the 3 types of kidney injury?

• vascular events

• tubular cell injury

• idiosyncratic

vascular kidney injury

• renal ischemia resulting from persistent vasoconstriction & ↓ glomerular capillary permeability

• initially causes pre-renal azotemia with no evidence of intrinsic renal injury

• ↓ renal blood flow and GFR can lead to tubular dysfunction secondary to anoxia

tubular cell injury

• tubular damage and/or tubular obstruction

  • casts form from:

    • myoglobin or hemoglobin

    • necrotic tubule cells

    • crystals like calcium oxalate

• casts may cause arteriolar vasoconstriction, tubular obstruction, and ↓ GFR

idiosyncratic kidney injury

• not dose-dependent

• unique to individual

mechanism of ethylene glycol toxicity

• ethylene glycol → can cause CNS depression, osmotic diuresis

• metabolized by alcohol dehydrogenase in liver → → glycolic acid (glycolate)

• glycolic acid = contributes to metabolic acidosis

• further metabolism into oxalic acid

  • oxalate complexes = nephrotoxicity

  • calcium oxalate crystals → renal tubular epithelium necrosis

stages/timeline of ethylene glycol toxicity

• stage 1: 30 min to 12 hrs post-ingestion

• stage 2: 12-24 hrs post-ingestion

  • animal can appear to be recovering

• stage 3: 24-72 hrs post-ingestion

which major organs/systems are affected by ethylene glycol toxicity?

• CNS

• urinary

detoxification treatment for ethylene glycol toxicity

• prevent absorption with emetics (before clinical signs appear)

• increase elimination with fluid therapy

  • activated charcoal NOT likely to be beneficial

treatment for preventing metabolism of ethylene glycol

• 4-methylpyrazole (4-MP, fomepizole) → inhibits alcohol dehydrogenase

• ethanol (20%) → competes for alcohol dehydrogenase

do not use 4-MP and ethanol together, or ethanol after treatment with 4-MP

supportive therapy for ethylene glycol toxicity

• fluid and electrolyte therapy

• peritoneal dialysis or hemodialysis

mechanism of NSAID toxicity

inhibits COX enzymes → block production of prostaglandins, including thromboxane A2 (TXA2)

• GI → ulcers/bleeding

• kidney → reduced blood flow & filtration, damage

• platelets (TXA2) → bleeding (decreased aggregation)

which major organs/systems are affected by NSAID toxicity?

• GI

• kidneys

• (CNS — high doses)

important toxicokinetic factors of ibuprofen (NSAIDs)

• differ based on type of NSAID

• metabolized by liver to inactive metabolites; excreted via urine

• enterohepatic recirculation — feces (prolongs half life)

detoxification treatment for NSAID toxicity

• prevent absorption with emetics (before clinical signs appear)

• increase elimination with activated charcoal, cathartics, and fluid therapy

supportive therapy for NSAID toxicity

• GI protectants — antacids, drugs to protect stomach lining, anti-emetic

• misoprostol — synthetic prostaglandin E1 analogue

• kidney — fluids, monitor blood BUN, creatinine; urinalysis → monitor for casts

• CNS — treat neurologic signs symptomatically

• severe cases may require blood transfusion

mechanism of grapes/raisin toxicity

• renal failure — proximal renal tubular epithelium

• only occurs in some dogs — idiosyncratic?

  • individual sensitivity among dogs

• tartaric acid levels in grapes vary by region, ripeness, variety, growing conditions

• clear dose-response relationship is not known

timeline of grapes/raisin toxicity

• acute signs: 6-12 hrs

• renal failure: 24-72 hrs

which major organs/systems are affected by grape/raisin toxicity?

• GI

• kidneys

treatment for grapes/raisin toxicity

• detoxification

  • prevent absorption with emetics (even several hours after ingestion since grapes do not easily break down)

  • increase elimination with activated charcoal, cathartics, and fluid therapy

• supportive therapy

  • kidney — fluids, monitor renal function & fluid balance

  • severe cases may require dialysis

mechanism of vitamin D₃ toxicity

vitamin D₃ (cholecalciferol) → metabolized to calcitriol → results in ↑ Ca²⁺ & P

• ↑ GI absorption

• ↑ release from bone

• ↑ kidney reabsorption

**calcitriol binds vitamin D receptors with 1000x greater affinity than vitamin D₃

effects of ↑ calcium (vitamin D₃ toxicity)

• vasoconstriction

• soft tissue mineralization (structural damage)

• ↓ cell membrane permeability

• ↓ GI motility

• ↓ cellular energy production

• cell death

timeline of vitamin D₃ toxicity

• initial signs: 18-36hrs

• advanced/severe: 2-3 days

which major organs/systems are affected by vitamin D₃ toxicity?

• GI

• kidneys

• cardiovascular

important vitamin D₃ toxicokinetics

rapidly absorbed, enterohepatic recirculation, excreted mainly via bile & feces

• fat soluble (also prolongs half-life)

detoxification treatments for vitamin D₃ toxicity

• prevent absorption with emetics (early, asymptomatic)

• increase elimination with activated charcoal and cathartics, diuretics

supportive therapy for vitamin D₃ toxicity

• kidney — fluid therapy, monitor renal function & fluid balance

• monitor/correct calcium & phosphorus levels

• IV lipid therapy

• steroids — reduce bone resorption

• GI support

• low calcium, low phosphorus diet

** long term treatment may be necessary